@article {10775, title = {Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.}, journal = {Genome Biol}, volume = {19}, year = {2018}, month = {2018 07 17}, pages = {87}, abstract = {

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.

RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874~individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.

CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

}, keywords = {ADAMTS Proteins, African Continental Ancestry Group, Animals, Connexin 43, Electrocardiography, European Continental Ancestry Group, Exome, Female, Gene Expression, Gene Expression Profiling, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Humans, Male, Mice, Middle Aged, Myocardium, Open Reading Frames, Polymorphism, Single Nucleotide, Whole Exome Sequencing}, issn = {1474-760X}, doi = {10.1186/s13059-018-1457-6}, author = {Prins, Bram P and Mead, Timothy J and Brody, Jennifer A and Sveinbjornsson, Gardar and Ntalla, Ioanna and Bihlmeyer, Nathan A and van den Berg, Marten and Bork-Jensen, Jette and Cappellani, Stefania and Van Duijvenboden, Stefan and Klena, Nikolai T and Gabriel, George C and Liu, Xiaoqin and Gulec, Cagri and Grarup, Niels and Haessler, Jeffrey and Hall, Leanne M and Iorio, Annamaria and Isaacs, Aaron and Li-Gao, Ruifang and Lin, Honghuang and Liu, Ching-Ti and Lyytik{\"a}inen, Leo-Pekka and Marten, Jonathan and Mei, Hao and M{\"u}ller-Nurasyid, Martina and Orini, Michele and Padmanabhan, Sandosh and Radmanesh, Farid and Ramirez, Julia and Robino, Antonietta and Schwartz, Molly and van Setten, Jessica and Smith, Albert V and Verweij, Niek and Warren, Helen R and Weiss, Stefan and Alonso, Alvaro and Arnar, David O and Bots, Michiel L and de Boer, Rudolf A and Dominiczak, Anna F and Eijgelsheim, Mark and Ellinor, Patrick T and Guo, Xiuqing and Felix, Stephan B and Harris, Tamara B and Hayward, Caroline and Heckbert, Susan R and Huang, Paul L and Jukema, J W and K{\"a}h{\"o}nen, Mika and Kors, Jan A and Lambiase, Pier D and Launer, Lenore J and Li, Man and Linneberg, Allan and Nelson, Christopher P and Pedersen, Oluf and Perez, Marco and Peters, Annette and Polasek, Ozren and Psaty, Bruce M and Raitakari, Olli T and Rice, Kenneth M and Rotter, Jerome I and Sinner, Moritz F and Soliman, Elsayed Z and Spector, Tim D and Strauch, Konstantin and Thorsteinsdottir, Unnur and Tinker, Andrew and Trompet, Stella and Uitterlinden, Andr{\'e} and Vaartjes, Ilonca and van der Meer, Peter and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wilson, James G and Xie, Zhijun and Asselbergs, Folkert W and D{\"o}rr, Marcus and van Duijn, Cornelia M and Gasparini, Paolo and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Hansen, Torben and K{\"a}{\"a}b, Stefan and Kanters, J{\o}rgen K and Kooperberg, Charles and Lehtim{\"a}ki, Terho and Lin, Henry J and Lubitz, Steven A and Mook-Kanamori, Dennis O and Conti, Francesco J and Newton-Cheh, Christopher H and Rosand, Jonathan and Rudan, Igor and Samani, Nilesh J and Sinagra, Gianfranco and Smith, Blair H and Holm, Hilma and Stricker, Bruno H and Ulivi, Sheila and Sotoodehnia, Nona and Apte, Suneel S and van der Harst, Pim and Stefansson, Kari and Munroe, Patricia B and Arking, Dan E and Lo, Cecilia W and Jamshidi, Yalda} } @article {10835, title = {PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 07 25}, pages = {2904}, abstract = {

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

}, keywords = {Atrial Function, Atrioventricular Node, Electrocardiography, Electrophysiological Phenomena, Female, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Mutation, Missense, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-018-04766-9}, author = {van Setten, Jessica and Brody, Jennifer A and Jamshidi, Yalda and Swenson, Brenton R and Butler, Anne M and Campbell, Harry and Del Greco, Fabiola M and Evans, Daniel S and Gibson, Quince and Gudbjartsson, Daniel F and Kerr, Kathleen F and Krijthe, Bouwe P and Lyytik{\"a}inen, Leo-Pekka and M{\"u}ller, Christian and M{\"u}ller-Nurasyid, Martina and Nolte, Ilja M and Padmanabhan, Sandosh and Ritchie, Marylyn D and Robino, Antonietta and Smith, Albert V and Steri, Maristella and Tanaka, Toshiko and Teumer, Alexander and Trompet, Stella and Ulivi, Sheila and Verweij, Niek and Yin, Xiaoyan and Arnar, David O and Asselbergs, Folkert W and Bader, Joel S and Barnard, John and Bis, Josh and Blankenberg, Stefan and Boerwinkle, Eric and Bradford, Yuki and Buckley, Brendan M and Chung, Mina K and Crawford, Dana and den Hoed, Marcel and Denny, Josh C and Dominiczak, Anna F and Ehret, Georg B and Eijgelsheim, Mark and Ellinor, Patrick T and Felix, Stephan B and Franco, Oscar H and Franke, Lude and Harris, Tamara B and Holm, Hilma and Ilaria, Gandin and Iorio, Annamaria and K{\"a}h{\"o}nen, Mika and Kolcic, Ivana and Kors, Jan A and Lakatta, Edward G and Launer, Lenore J and Lin, Honghuang and Lin, Henry J and Loos, Ruth J F and Lubitz, Steven A and Macfarlane, Peter W and Magnani, Jared W and Leach, Irene Mateo and Meitinger, Thomas and Mitchell, Braxton D and Munzel, Thomas and Papanicolaou, George J and Peters, Annette and Pfeufer, Arne and Pramstaller, Peter P and Raitakari, Olli T and Rotter, Jerome I and Rudan, Igor and Samani, Nilesh J and Schlessinger, David and Silva Aldana, Claudia T and Sinner, Moritz F and Smith, Jonathan D and Snieder, Harold and Soliman, Elsayed Z and Spector, Timothy D and Stott, David J and Strauch, Konstantin and Tarasov, Kirill V and Thorsteinsdottir, Unnur and Uitterlinden, Andr{\'e} G and Van Wagoner, David R and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Jan Westra, Harm and Wild, Philipp S and Zeller, Tanja and Alonso, Alvaro and Avery, Christy L and Bandinelli, Stefania and Benjamin, Emelia J and Cucca, Francesco and D{\"o}rr, Marcus and Ferrucci, Luigi and Gasparini, Paolo and Gudnason, Vilmundur and Hayward, Caroline and Heckbert, Susan R and Hicks, Andrew A and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and Lehtim{\"a}ki, Terho and Liu, Yongmei and Munroe, Patricia B and Parsa, Afshin and Polasek, Ozren and Psaty, Bruce M and Roden, Dan M and Schnabel, Renate B and Sinagra, Gianfranco and Stefansson, Kari and Stricker, Bruno H and van der Harst, Pim and van Duijn, Cornelia M and Wilson, James F and Gharib, Sina A and de Bakker, Paul I W and Isaacs, Aaron and Arking, Dan E and Sotoodehnia, Nona} } @article {10481, title = {1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {2017 04 28}, pages = {45040}, abstract = {

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5\% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 {\texttimes} 10 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

}, keywords = {Computational Biology, Gene Frequency, Genetic Loci, Genome, Human, Genome-Wide Association Study, Genotyping Techniques, Humans, Kidney, Polymorphism, Single Nucleotide}, issn = {2045-2322}, doi = {10.1038/srep45040}, author = {Gorski, Mathias and van der Most, Peter J and Teumer, Alexander and Chu, Audrey Y and Li, Man and Mijatovic, Vladan and Nolte, Ilja M and Cocca, Massimiliano and Taliun, Daniel and Gomez, Felicia and Li, Yong and Tayo, Bamidele and Tin, Adrienne and Feitosa, Mary F and Aspelund, Thor and Attia, John and Biffar, Reiner and Bochud, Murielle and Boerwinkle, Eric and Borecki, Ingrid and Bottinger, Erwin P and Chen, Ming-Huei and Chouraki, Vincent and Ciullo, Marina and Coresh, Josef and Cornelis, Marilyn C and Curhan, Gary C and d{\textquoteright}Adamo, Adamo Pio and Dehghan, Abbas and Dengler, Laura and Ding, Jingzhong and Eiriksdottir, Gudny and Endlich, Karlhans and Enroth, Stefan and Esko, T{\~o}nu and Franco, Oscar H and Gasparini, Paolo and Gieger, Christian and Girotto, Giorgia and Gottesman, Omri and Gudnason, Vilmundur and Gyllensten, Ulf and Hancock, Stephen J and Harris, Tamara B and Helmer, Catherine and H{\"o}llerer, Simon and Hofer, Edith and Hofman, Albert and Holliday, Elizabeth G and Homuth, Georg and Hu, Frank B and Huth, Cornelia and Hutri-K{\"a}h{\"o}nen, Nina and Hwang, Shih-Jen and Imboden, Medea and Johansson, {\r A}sa and K{\"a}h{\"o}nen, Mika and K{\"o}nig, Wolfgang and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kumar, Ashish and Kutalik, Zolt{\'a}n and Lambert, Jean-Charles and Launer, Lenore J and Lehtim{\"a}ki, Terho and de Borst, Martin and Navis, Gerjan and Swertz, Morris and Liu, Yongmei and Lohman, Kurt and Loos, Ruth J F and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and McEvoy, Mark A and Meisinger, Christa and Meitinger, Thomas and Metspalu, Andres and Metzger, Marie and Mihailov, Evelin and Mitchell, Paul and Nauck, Matthias and Oldehinkel, Albertine J and Olden, Matthias and Wjh Penninx, Brenda and Pistis, Giorgio and Pramstaller, Peter P and Probst-Hensch, Nicole and Raitakari, Olli T and Rettig, Rainer and Ridker, Paul M and Rivadeneira, Fernando and Robino, Antonietta and Rosas, Sylvia E and Ruderfer, Douglas and Ruggiero, Daniela and Saba, Yasaman and Sala, Cinzia and Schmidt, Helena and Schmidt, Reinhold and Scott, Rodney J and Sedaghat, Sanaz and Smith, Albert V and Sorice, Rossella and Stengel, B{\'e}n{\'e}dicte and Stracke, Sylvia and Strauch, Konstantin and Toniolo, Daniela and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Viikari, Jorma S and V{\"o}lker, Uwe and Vollenweider, Peter and V{\"o}lzke, Henry and Vuckovic, Dragana and Waldenberger, Melanie and Jin Wang, Jie and Yang, Qiong and Chasman, Daniel I and Tromp, Gerard and Snieder, Harold and Heid, Iris M and Fox, Caroline S and K{\"o}ttgen, Anna and Pattaro, Cristian and B{\"o}ger, Carsten A and Fuchsberger, Christian} } @article {10572, title = { and Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.}, journal = {J Am Soc Nephrol}, volume = {28}, year = {2017}, month = {2017 Mar}, pages = {981-994}, abstract = {

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7{\texttimes}10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4{\texttimes}10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

}, keywords = {Animals, Exome, Genetic Loci, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Protein Tyrosine Phosphatases, Proto-Oncogene Proteins, Son of Sevenless Proteins, Zebrafish}, issn = {1533-3450}, doi = {10.1681/ASN.2016020131}, author = {Li, Man and Li, Yong and Weeks, Olivia and Mijatovic, Vladan and Teumer, Alexander and Huffman, Jennifer E and Tromp, Gerard and Fuchsberger, Christian and Gorski, Mathias and Lyytik{\"a}inen, Leo-Pekka and Nutile, Teresa and Sedaghat, Sanaz and Sorice, Rossella and Tin, Adrienne and Yang, Qiong and Ahluwalia, Tarunveer S and Arking, Dan E and Bihlmeyer, Nathan A and B{\"o}ger, Carsten A and Carroll, Robert J and Chasman, Daniel I and Cornelis, Marilyn C and Dehghan, Abbas and Faul, Jessica D and Feitosa, Mary F and Gambaro, Giovanni and Gasparini, Paolo and Giulianini, Franco and Heid, Iris and Huang, Jinyan and Imboden, Medea and Jackson, Anne U and Jeff, Janina and Jhun, Min A and Katz, Ronit and Kifley, Annette and Kilpel{\"a}inen, Tuomas O and Kumar, Ashish and Laakso, Markku and Li-Gao, Ruifang and Lohman, Kurt and Lu, Yingchang and M{\"a}gi, Reedik and Malerba, Giovanni and Mihailov, Evelin and Mohlke, Karen L and Mook-Kanamori, Dennis O and Robino, Antonietta and Ruderfer, Douglas and Salvi, Erika and Schick, Ursula M and Schulz, Christina-Alexandra and Smith, Albert V and Smith, Jennifer A and Traglia, Michela and Yerges-Armstrong, Laura M and Zhao, Wei and Goodarzi, Mark O and Kraja, Aldi T and Liu, Chunyu and Wessel, Jennifer and Boerwinkle, Eric and Borecki, Ingrid B and Bork-Jensen, Jette and Bottinger, Erwin P and Braga, Daniele and Brandslund, Ivan and Brody, Jennifer A and Campbell, Archie and Carey, David J and Christensen, Cramer and Coresh, Josef and Crook, Errol and Curhan, Gary C and Cusi, Daniele and de Boer, Ian H and de Vries, Aiko P J and Denny, Joshua C and Devuyst, Olivier and Dreisbach, Albert W and Endlich, Karlhans and Esko, T{\~o}nu and Franco, Oscar H and Fulop, Tibor and Gerhard, Glenn S and Gl{\"u}mer, Charlotte and Gottesman, Omri and Grarup, Niels and Gudnason, Vilmundur and Hansen, Torben and Harris, Tamara B and Hayward, Caroline and Hocking, Lynne and Hofman, Albert and Hu, Frank B and Husemoen, Lise Lotte N and Jackson, Rebecca D and J{\o}rgensen, Torben and J{\o}rgensen, Marit E and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and K{\"o}nig, Wolfgang and Kooperberg, Charles and Kriebel, Jennifer and Launer, Lenore J and Lauritzen, Torsten and Lehtim{\"a}ki, Terho and Levy, Daniel and Linksted, Pamela and Linneberg, Allan and Liu, Yongmei and Loos, Ruth J F and Lupo, Antonio and Meisinger, Christine and Melander, Olle and Metspalu, Andres and Mitchell, Paul and Nauck, Matthias and N{\"u}rnberg, Peter and Orho-Melander, Marju and Parsa, Afshin and Pedersen, Oluf and Peters, Annette and Peters, Ulrike and Polasek, Ozren and Porteous, David and Probst-Hensch, Nicole M and Psaty, Bruce M and Qi, Lu and Raitakari, Olli T and Reiner, Alex P and Rettig, Rainer and Ridker, Paul M and Rivadeneira, Fernando and Rossouw, Jacques E and Schmidt, Frank and Siscovick, David and Soranzo, Nicole and Strauch, Konstantin and Toniolo, Daniela and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Velayutham, Dinesh and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wang, Jie Jin and Weir, David R and Witte, Daniel and Kuivaniemi, Helena and Fox, Caroline S and Franceschini, Nora and Goessling, Wolfram and K{\"o}ttgen, Anna and Chu, Audrey Y} } @article {10568, title = {Common variants in CLDN14 are associated with differential excretion of magnesium over calcium in urine.}, journal = {Pflugers Arch}, volume = {469}, year = {2017}, month = {2017 01}, pages = {91-103}, abstract = {

The nature and importance of genetic factors regulating the differential handling of Ca and Mg by the renal tubule in the general population are poorly defined. We conducted a genome-wide meta-analysis of urinary magnesium-to-calcium ratio to identify associated common genetic variants. We included 9320 adults of European descent from four genetic isolates and three urban cohorts. Urinary magnesium and calcium concentrations were measured centrally in spot urine, and each study conducted linear regression analysis of urinary magnesium-to-calcium ratio on ~2.5 million single-nucleotide polymorphisms (SNPs) using an additive model. We investigated, in mouse, the renal expression profile of the top candidate gene and its variation upon changes in dietary magnesium. The genome-wide analysis evidenced a top locus (rs172639, p~=~1.7~{\texttimes}~10), encompassing CLDN14, the gene coding for claudin-14, that was genome-wide significant when using urinary magnesium-to-calcium ratio, but not either one taken separately. In mouse, claudin-14 is expressed in the distal nephron segments specifically handling magnesium, and its expression is regulated by chronic changes in dietary magnesium content. A genome-wide approach identified common variants in the CLDN14 gene exerting a robust influence on the differential excretion of Mg over Ca in urine. These data highlight the power of urinary electrolyte ratios to unravel genetic determinants of renal tubular function. Coupled with mouse experiments, these results support a major role for claudin-14, a gene associated with kidney stones, in the differential paracellular handling of divalent cations by the renal tubule.

}, keywords = {Animals, Calcium, Claudins, Humans, Kidney Tubules, Magnesium, Polymorphism, Single Nucleotide, Urine}, issn = {1432-2013}, doi = {10.1007/s00424-016-1913-7}, author = {Corre, Tanguy and Olinger, Eric and Harris, Sarah E and Traglia, Michela and Ulivi, Sheila and Lenarduzzi, Stefania and Belge, Hendrica and Youhanna, Sonia and Tokonami, Natsuko and Bonny, Olivier and Houillier, Pascal and Polasek, Ozren and Deary, Ian J and Starr, John M and Toniolo, Daniela and Gasparini, Paolo and Vollenweider, Peter and Hayward, Caroline and Bochud, Murielle and Devuyst, Olivier} } @article {10556, title = {Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Jun}, pages = {834-841}, abstract = {

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to \~{}370,000 women, we identify 389 independent signals (P < 5 {\texttimes} 10) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain \~{}7.4\% of the population variance in age at menarche, corresponding to \~{}25\% of the estimated heritability. We implicate \~{}250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

}, keywords = {Adolescent, Age Factors, Body Mass Index, Databases, Genetic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomic Imprinting, Humans, Intercellular Signaling Peptides and Proteins, Male, Membrane Proteins, Menarche, Neoplasms, Polymorphism, Single Nucleotide, Puberty, Quantitative Trait Loci, Ribonucleoproteins, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.3841}, author = {Day, Felix R and Thompson, Deborah J and Helgason, Hannes and Chasman, Daniel I and Finucane, Hilary and Sulem, Patrick and Ruth, Katherine S and Whalen, Sean and Sarkar, Abhishek K and Albrecht, Eva and Altmaier, Elisabeth and Amini, Marzyeh and Barbieri, Caterina M and Boutin, Thibaud and Campbell, Archie and Demerath, Ellen and Giri, Ayush and He, Chunyan and Hottenga, Jouke J and Karlsson, Robert and Kolcic, Ivana and Loh, Po-Ru and Lunetta, Kathryn L and Mangino, Massimo and Marco, Brumat and McMahon, George and Medland, Sarah E and Nolte, Ilja M and Noordam, Raymond and Nutile, Teresa and Paternoster, Lavinia and Perjakova, Natalia and Porcu, Eleonora and Rose, Lynda M and Schraut, Katharina E and Segr{\`e}, Ayellet V and Smith, Albert V and Stolk, Lisette and Teumer, Alexander and Andrulis, Irene L and Bandinelli, Stefania and Beckmann, Matthias W and Benitez, Javier and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bojesen, Stig E and Bolla, Manjeet K and Brand, Judith S and Brauch, Hiltrud and Brenner, Hermann and Broer, Linda and Br{\"u}ning, Thomas and Buring, Julie E and Campbell, Harry and Catamo, Eulalia and Chanock, Stephen and Chenevix-Trench, Georgia and Corre, Tanguy and Couch, Fergus J and Cousminer, Diana L and Cox, Angela and Crisponi, Laura and Czene, Kamila and Davey Smith, George and de Geus, Eco J C N and de Mutsert, Ren{\'e}e and De Vivo, Immaculata and Dennis, Joe and Devilee, Peter and Dos-Santos-Silva, Isabel and Dunning, Alison M and Eriksson, Johan G and Fasching, Peter A and Fern{\'a}ndez-Rhodes, Lindsay and Ferrucci, Luigi and Flesch-Janys, Dieter and Franke, Lude and Gabrielson, Marike and Gandin, Ilaria and Giles, Graham G and Grallert, Harald and Gudbjartsson, Daniel F and Guenel, Pascal and Hall, Per and Hallberg, Emily and Hamann, Ute and Harris, Tamara B and Hartman, Catharina A and Heiss, Gerardo and Hooning, Maartje J and Hopper, John L and Hu, Frank and Hunter, David J and Ikram, M Arfan and Im, Hae Kyung and J{\"a}rvelin, Marjo-Riitta and Joshi, Peter K and Karasik, David and Kellis, Manolis and Kutalik, Zolt{\'a}n and LaChance, Genevieve and Lambrechts, Diether and Langenberg, Claudia and Launer, Lenore J and Laven, Joop S E and Lenarduzzi, Stefania and Li, Jingmei and Lind, Penelope A and Lindstr{\"o}m, Sara and Liu, Yongmei and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Mannermaa, Arto and Mbarek, Hamdi and McCarthy, Mark I and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Metspalu, Andres and Michailidou, Kyriaki and Milani, Lili and Milne, Roger L and Montgomery, Grant W and Mulligan, Anna M and Nalls, Mike A and Navarro, Pau and Nevanlinna, Heli and Nyholt, Dale R and Oldehinkel, Albertine J and O{\textquoteright}Mara, Tracy A and Padmanabhan, Sandosh and Palotie, Aarno and Pedersen, Nancy and Peters, Annette and Peto, Julian and Pharoah, Paul D P and Pouta, Anneli and Radice, Paolo and Rahman, Iffat and Ring, Susan M and Robino, Antonietta and Rosendaal, Frits R and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Sala, Cinzia F and Schmidt, Marjanka K and Scott, Robert A and Shah, Mitul and Sorice, Rossella and Southey, Melissa C and Sovio, Ulla and Stampfer, Meir and Steri, Maristella and Strauch, Konstantin and Tanaka, Toshiko and Tikkanen, Emmi and Timpson, Nicholas J and Traglia, Michela and Truong, Therese and Tyrer, Jonathan P and Uitterlinden, Andr{\'e} G and Edwards, Digna R Velez and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and Wang, Qin and Widen, Elisabeth and van Dijk, Ko Willems and Willemsen, Gonneke and Winqvist, Robert and Wolffenbuttel, Bruce H R and Zhao, Jing Hua and Zoledziewska, Magdalena and Zygmunt, Marek and Alizadeh, Behrooz Z and Boomsma, Dorret I and Ciullo, Marina and Cucca, Francesco and Esko, T{\~o}nu and Franceschini, Nora and Gieger, Christian and Gudnason, Vilmundur and Hayward, Caroline and Kraft, Peter and Lawlor, Debbie A and Magnusson, Patrik K E and Martin, Nicholas G and Mook-Kanamori, Dennis O and Nohr, Ellen A and Polasek, Ozren and Porteous, David and Price, Alkes L and Ridker, Paul M and Snieder, Harold and Spector, Tim D and St{\"o}ckl, Doris and Toniolo, Daniela and Ulivi, Sheila and Visser, Jenny A and V{\"o}lzke, Henry and Wareham, Nicholas J and Wilson, James F and Spurdle, Amanda B and Thorsteindottir, Unnur and Pollard, Katherine S and Easton, Douglas F and Tung, Joyce Y and Chang-Claude, Jenny and Hinds, David and Murray, Anna and Murabito, Joanne M and Stefansson, Kari and Ong, Ken K and Perry, John R B} } @article {10493, title = {Rare and low-frequency coding variants alter human adult height.}, journal = {Nature}, volume = {542}, year = {2017}, month = {2017 02 09}, pages = {186-190}, abstract = {

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8\%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

}, keywords = {ADAMTS Proteins, Adult, Alleles, Body Height, Cell Adhesion Molecules, Female, Gene Frequency, Genetic Variation, Genome, Human, Glycoproteins, Glycosaminoglycans, Hedgehog Proteins, Humans, Intercellular Signaling Peptides and Proteins, Interferon Regulatory Factors, Interleukin-11 Receptor alpha Subunit, Male, Multifactorial Inheritance, NADPH Oxidase 4, NADPH Oxidases, Phenotype, Pregnancy-Associated Plasma Protein-A, Procollagen N-Endopeptidase, Proteoglycans, Proteolysis, Receptors, Androgen, Somatomedins}, issn = {1476-4687}, doi = {10.1038/nature21039}, author = {Marouli, Eirini and Graff, Mariaelisa and Medina-Gomez, Carolina and Lo, Ken Sin and Wood, Andrew R and Kjaer, Troels R and Fine, Rebecca S and Lu, Yingchang and Schurmann, Claudia and Highland, Heather M and R{\"u}eger, Sina and Thorleifsson, Gudmar and Justice, Anne E and Lamparter, David and Stirrups, Kathleen E and Turcot, Val{\'e}rie and Young, Kristin L and Winkler, Thomas W and Esko, T{\~o}nu and Karaderi, Tugce and Locke, Adam E and Masca, Nicholas G D and Ng, Maggie C Y and Mudgal, Poorva and Rivas, Manuel A and Vedantam, Sailaja and Mahajan, Anubha and Guo, Xiuqing and Abecasis, Goncalo and Aben, Katja K and Adair, Linda S and Alam, Dewan S and Albrecht, Eva and Allin, Kristine H and Allison, Matthew and Amouyel, Philippe and Appel, Emil V and Arveiler, Dominique and Asselbergs, Folkert W and Auer, Paul L and Balkau, Beverley and Banas, Bernhard and Bang, Lia E and Benn, Marianne and Bergmann, Sven and Bielak, Lawrence F and Bl{\"u}her, Matthias and Boeing, Heiner and Boerwinkle, Eric and B{\"o}ger, Carsten A and Bonnycastle, Lori L and Bork-Jensen, Jette and Bots, Michiel L and Bottinger, Erwin P and Bowden, Donald W and Brandslund, Ivan and Breen, Gerome and Brilliant, Murray H and Broer, Linda and Burt, Amber A and Butterworth, Adam S and Carey, David J and Caulfield, Mark J and Chambers, John C and Chasman, Daniel I and Chen, Yii-Der Ida and Chowdhury, Rajiv and Christensen, Cramer and Chu, Audrey Y and Cocca, Massimiliano and Collins, Francis S and Cook, James P and Corley, Janie and Galbany, Jordi Corominas and Cox, Amanda J and Cuellar-Partida, Gabriel and Danesh, John and Davies, Gail and de Bakker, Paul I W and de Borst, Gert J and de Denus, Simon and de Groot, Mark C H and de Mutsert, Ren{\'e}e and Deary, Ian J and Dedoussis, George and Demerath, Ellen W and den Hollander, Anneke I and Dennis, Joe G and Di Angelantonio, Emanuele and Drenos, Fotios and Du, Mengmeng and Dunning, Alison M and Easton, Douglas F and Ebeling, Tapani and Edwards, Todd L and Ellinor, Patrick T and Elliott, Paul and Evangelou, Evangelos and Farmaki, Aliki-Eleni and Faul, Jessica D and Feitosa, Mary F and Feng, Shuang and Ferrannini, Ele and Ferrario, Marco M and Ferri{\`e}res, Jean and Florez, Jose C and Ford, Ian and Fornage, Myriam and Franks, Paul W and Frikke-Schmidt, Ruth and Galesloot, Tessel E and Gan, Wei and Gandin, Ilaria and Gasparini, Paolo and Giedraitis, Vilmantas and Giri, Ayush and Girotto, Giorgia and Gordon, Scott D and Gordon-Larsen, Penny and Gorski, Mathias and Grarup, Niels and Grove, Megan L and Gudnason, Vilmundur and Gustafsson, Stefan and Hansen, Torben and Harris, Kathleen Mullan and Harris, Tamara B and Hattersley, Andrew T and Hayward, Caroline and He, Liang and Heid, Iris M and Heikkil{\"a}, Kauko and Helgeland, {\O}yvind and Hernesniemi, Jussi and Hewitt, Alex W and Hocking, Lynne J and Hollensted, Mette and Holmen, Oddgeir L and Hovingh, G Kees and Howson, Joanna M M and Hoyng, Carel B and Huang, Paul L and Hveem, Kristian and Ikram, M Arfan and Ingelsson, Erik and Jackson, Anne U and Jansson, Jan-H{\r a}kan and Jarvik, Gail P and Jensen, Gorm B and Jhun, Min A and Jia, Yucheng and Jiang, Xuejuan and Johansson, Stefan and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and Jousilahti, Pekka and Jukema, J Wouter and Kahali, Bratati and Kahn, Ren{\'e} S and K{\"a}h{\"o}nen, Mika and Kamstrup, Pia R and Kanoni, Stavroula and Kaprio, Jaakko and Karaleftheri, Maria and Kardia, Sharon L R and Karpe, Fredrik and Kee, Frank and Keeman, Renske and Kiemeney, Lambertus A and Kitajima, Hidetoshi and Kluivers, Kirsten B and Kocher, Thomas and Komulainen, Pirjo and Kontto, Jukka and Kooner, Jaspal S and Kooperberg, Charles and Kovacs, Peter and Kriebel, Jennifer and Kuivaniemi, Helena and K{\"u}ry, S{\'e}bastien and Kuusisto, Johanna and La Bianca, Martina and Laakso, Markku and Lakka, Timo A and Lange, Ethan M and Lange, Leslie A and Langefeld, Carl D and Langenberg, Claudia and Larson, Eric B and Lee, I-Te and Lehtim{\"a}ki, Terho and Lewis, Cora E and Li, Huaixing and Li, Jin and Li-Gao, Ruifang and Lin, Honghuang and Lin, Li-An and Lin, Xu and Lind, Lars and Lindstr{\"o}m, Jaana and Linneberg, Allan and Liu, Yeheng and Liu, Yongmei and Lophatananon, Artitaya and Luan, Jian{\textquoteright}an and Lubitz, Steven A and Lyytik{\"a}inen, Leo-Pekka and Mackey, David A and Madden, Pamela A F and Manning, Alisa K and M{\"a}nnist{\"o}, Satu and Marenne, Ga{\"e}lle and Marten, Jonathan and Martin, Nicholas G and Mazul, Angela L and Meidtner, Karina and Metspalu, Andres and Mitchell, Paul and Mohlke, Karen L and Mook-Kanamori, Dennis O and Morgan, Anna and Morris, Andrew D and Morris, Andrew P and M{\"u}ller-Nurasyid, Martina and Munroe, Patricia B and Nalls, Mike A and Nauck, Matthias and Nelson, Christopher P and Neville, Matt and Nielsen, Sune F and Nikus, Kjell and Nj{\o}lstad, P{\r a}l R and Nordestgaard, B{\o}rge G and Ntalla, Ioanna and O{\textquoteright}Connel, Jeffrey R and Oksa, Heikki and Loohuis, Loes M Olde and Ophoff, Roel A and Owen, Katharine R and Packard, Chris J and Padmanabhan, Sandosh and Palmer, Colin N A and Pasterkamp, Gerard and Patel, Aniruddh P and Pattie, Alison and Pedersen, Oluf and Peissig, Peggy L and Peloso, Gina M and Pennell, Craig E and Perola, Markus and Perry, James A and Perry, John R B and Person, Thomas N and Pirie, Ailith and Polasek, Ozren and Posthuma, Danielle and Raitakari, Olli T and Rasheed, Asif and Rauramaa, Rainer and Reilly, Dermot F and Reiner, Alex P and Renstrom, Frida and Ridker, Paul M and Rioux, John D and Robertson, Neil and Robino, Antonietta and Rolandsson, Olov and Rudan, Igor and Ruth, Katherine S and Saleheen, Danish and Salomaa, Veikko and Samani, Nilesh J and Sandow, Kevin and Sapkota, Yadav and Sattar, Naveed and Schmidt, Marjanka K and Schreiner, Pamela J and Schulze, Matthias B and Scott, Robert A and Segura-Lepe, Marcelo P and Shah, Svati and Sim, Xueling and Sivapalaratnam, Suthesh and Small, Kerrin S and Smith, Albert Vernon and Smith, Jennifer A and Southam, Lorraine and Spector, Timothy D and Speliotes, Elizabeth K and Starr, John M and Steinthorsdottir, Valgerdur and Stringham, Heather M and Stumvoll, Michael and Surendran, Praveen and {\textquoteright}t Hart, Leen M and Tansey, Katherine E and Tardif, Jean-Claude and Taylor, Kent D and Teumer, Alexander and Thompson, Deborah J and Thorsteinsdottir, Unnur and Thuesen, Betina H and T{\"o}njes, Anke and Tromp, Gerard and Trompet, Stella and Tsafantakis, Emmanouil and Tuomilehto, Jaakko and Tybjaerg-Hansen, Anne and Tyrer, Jonathan P and Uher, Rudolf and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and van der Laan, Sander W and Van Der Leij, Andries R and van Duijn, Cornelia M and van Schoor, Natasja M and van Setten, Jessica and Varbo, Anette and Varga, Tibor V and Varma, Rohit and Edwards, Digna R Velez and Vermeulen, Sita H and Vestergaard, Henrik and Vitart, Veronique and Vogt, Thomas F and Vozzi, Diego and Walker, Mark and Wang, Feijie and Wang, Carol A and Wang, Shuai and Wang, Yiqin and Wareham, Nicholas J and Warren, Helen R and Wessel, Jennifer and Willems, Sara M and Wilson, James G and Witte, Daniel R and Woods, Michael O and Wu, Ying and Yaghootkar, Hanieh and Yao, Jie and Yao, Pang and Yerges-Armstrong, Laura M and Young, Robin and Zeggini, Eleftheria and Zhan, Xiaowei and Zhang, Weihua and Zhao, Jing Hua and Zhao, Wei and Zhao, Wei and Zheng, He and Zhou, Wei and Rotter, Jerome I and Boehnke, Michael and Kathiresan, Sekar and McCarthy, Mark I and Willer, Cristen J and Stefansson, Kari and Borecki, Ingrid B and Liu, Dajiang J and North, Kari E and Heard-Costa, Nancy L and Pers, Tune H and Lindgren, Cecilia M and Oxvig, Claus and Kutalik, Zolt{\'a}n and Rivadeneira, Fernando and Loos, Ruth J F and Frayling, Timothy M and Hirschhorn, Joel N and Deloukas, Panos and Lettre, Guillaume} } @article {8304, title = {Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016}, pages = {10023}, abstract = {

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

}, keywords = {Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic}, issn = {2041-1723}, doi = {10.1038/ncomms10023}, author = {Pattaro, Cristian and Teumer, Alexander and Gorski, Mathias and Chu, Audrey Y and Li, Man and Mijatovic, Vladan and Garnaas, Maija and Tin, Adrienne and Sorice, Rossella and Li, Yong and Taliun, Daniel and Olden, Matthias and Foster, Meredith and Yang, Qiong and Chen, Ming-Huei and Pers, Tune H and Johnson, Andrew D and Ko, Yi-An and Fuchsberger, Christian and Tayo, Bamidele and Nalls, Michael and Feitosa, Mary F and Isaacs, Aaron and Dehghan, Abbas and d{\textquoteright}Adamo, Pio and Adeyemo, Adebowale and Dieffenbach, Aida Karina and Zonderman, Alan B and Nolte, Ilja M and van der Most, Peter J and Wright, Alan F and Shuldiner, Alan R and Morrison, Alanna C and Hofman, Albert and Smith, Albert V and Dreisbach, Albert W and Franke, Andre and Uitterlinden, Andr{\'e} G and Metspalu, Andres and T{\"o}njes, Anke and Lupo, Antonio and Robino, Antonietta and Johansson, {\r A}sa and Demirkan, Ayse and Kollerits, Barbara and Freedman, Barry I and Ponte, Belen and Oostra, Ben A and Paulweber, Bernhard and Kr{\"a}mer, Bernhard K and Mitchell, Braxton D and Buckley, Brendan M and Peralta, Carmen A and Hayward, Caroline and Helmer, Catherine and Rotimi, Charles N and Shaffer, Christian M and M{\"u}ller, Christian and Sala, Cinzia and van Duijn, Cornelia M and Saint-Pierre, Aude and Ackermann, Daniel and Shriner, Daniel and Ruggiero, Daniela and Toniolo, Daniela and Lu, Yingchang and Cusi, Daniele and Czamara, Darina and Ellinghaus, David and Siscovick, David S and Ruderfer, Douglas and Gieger, Christian and Grallert, Harald and Rochtchina, Elena and Atkinson, Elizabeth J and Holliday, Elizabeth G and Boerwinkle, Eric and Salvi, Erika and Bottinger, Erwin P and Murgia, Federico and Rivadeneira, Fernando and Ernst, Florian and Kronenberg, Florian and Hu, Frank B and Navis, Gerjan J and Curhan, Gary C and Ehret, George B and Homuth, Georg and Coassin, Stefan and Thun, Gian-Andri and Pistis, Giorgio and Gambaro, Giovanni and Malerba, Giovanni and Montgomery, Grant W and Eiriksdottir, Gudny and Jacobs, Gunnar and Li, Guo and Wichmann, H-Erich and Campbell, Harry and Schmidt, Helena and Wallaschofski, Henri and V{\"o}lzke, Henry and Brenner, Hermann and Kroemer, Heyo K and Kramer, Holly and Lin, Honghuang and Leach, I Mateo and Ford, Ian and Guessous, Idris and Rudan, Igor and Prokopenko, Inga and Borecki, Ingrid and Heid, Iris M and Kolcic, Ivana and Persico, Ivana and Jukema, J Wouter and Wilson, James F and Felix, Janine F and Divers, Jasmin and Lambert, Jean-Charles and Stafford, Jeanette M and Gaspoz, Jean-Michel and Smith, Jennifer A and Faul, Jessica D and Wang, Jie Jin and Ding, Jingzhong and Hirschhorn, Joel N and Attia, John and Whitfield, John B and Chalmers, John and Viikari, Jorma and Coresh, Josef and Denny, Joshua C and Karjalainen, Juha and Fernandes, Jyotika K and Endlich, Karlhans and Butterbach, Katja and Keene, Keith L and Lohman, Kurt and Portas, Laura and Launer, Lenore J and Lyytik{\"a}inen, Leo-Pekka and Yengo, Loic and Franke, Lude and Ferrucci, Luigi and Rose, Lynda M and Kedenko, Lyudmyla and Rao, Madhumathi and Struchalin, Maksim and Kleber, Marcus E and Cavalieri, Margherita and Haun, Margot and Cornelis, Marilyn C and Ciullo, Marina and Pirastu, Mario and de Andrade, Mariza and McEvoy, Mark A and Woodward, Mark and Adam, Martin and Cocca, Massimiliano and Nauck, Matthias and Imboden, Medea and Waldenberger, Melanie and Pruijm, Menno and Metzger, Marie and Stumvoll, Michael and Evans, Michele K and Sale, Michele M and K{\"a}h{\"o}nen, Mika and Boban, Mladen and Bochud, Murielle and Rheinberger, Myriam and Verweij, Niek and Bouatia-Naji, Nabila and Martin, Nicholas G and Hastie, Nick and Probst-Hensch, Nicole and Soranzo, Nicole and Devuyst, Olivier and Raitakari, Olli and Gottesman, Omri and Franco, Oscar H and Polasek, Ozren and Gasparini, Paolo and Munroe, Patricia B and Ridker, Paul M and Mitchell, Paul and Muntner, Paul and Meisinger, Christa and Smit, Johannes H and Kovacs, Peter and Wild, Philipp S and Froguel, Philippe and Rettig, Rainer and M{\"a}gi, Reedik and Biffar, Reiner and Schmidt, Reinhold and Middelberg, Rita P S and Carroll, Robert J and Penninx, Brenda W and Scott, Rodney J and Katz, Ronit and Sedaghat, Sanaz and Wild, Sarah H and Kardia, Sharon L R and Ulivi, Sheila and Hwang, Shih-Jen and Enroth, Stefan and Kloiber, Stefan and Trompet, Stella and Stengel, B{\'e}n{\'e}dicte and Hancock, Stephen J and Turner, Stephen T and Rosas, Sylvia E and Stracke, Sylvia and Harris, Tamara B and Zeller, Tanja and Zemunik, Tatijana and Lehtim{\"a}ki, Terho and Illig, Thomas and Aspelund, Thor and Nikopensius, Tiit and Esko, T{\~o}nu and Tanaka, Toshiko and Gyllensten, Ulf and V{\"o}lker, Uwe and Emilsson, Valur and Vitart, Veronique and Aalto, Ville and Gudnason, Vilmundur and Chouraki, Vincent and Chen, Wei-Min and Igl, Wilmar and M{\"a}rz, Winfried and Koenig, Wolfgang and Lieb, Wolfgang and Loos, Ruth J F and Liu, Yongmei and Snieder, Harold and Pramstaller, Peter P and Parsa, Afshin and O{\textquoteright}Connell, Jeffrey R and Susztak, Katalin and Hamet, Pavel and Tremblay, Johanne and de Boer, Ian H and B{\"o}ger, Carsten A and Goessling, Wolfram and Chasman, Daniel I and K{\"o}ttgen, Anna and Kao, W H Linda and Fox, Caroline S} } @article {8484, title = {Genome-wide association study identifies 74 loci associated with educational attainment.}, journal = {Nature}, volume = {533}, year = {2016}, month = {2016 May 26}, pages = {539-42}, abstract = {

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20\% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

}, keywords = {Alzheimer Disease, Bipolar Disorder, Brain, Cognition, Computational Biology, Educational Status, Fetus, Gene Expression Regulation, Gene-Environment Interaction, Genome-Wide Association Study, Great Britain, Humans, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Schizophrenia}, issn = {1476-4687}, doi = {10.1038/nature17671}, author = {Okbay, Aysu and Beauchamp, Jonathan P and Fontana, Mark Alan and Lee, James J and Pers, Tune H and Rietveld, Cornelius A and Turley, Patrick and Chen, Guo-Bo and Emilsson, Valur and Meddens, S Fleur W and Oskarsson, Sven and Pickrell, Joseph K and Thom, Kevin and Timshel, Pascal and de Vlaming, Ronald and Abdellaoui, Abdel and Ahluwalia, Tarunveer S and Bacelis, Jonas and Baumbach, Clemens and Bjornsdottir, Gyda and Brandsma, Johannes H and Pina Concas, Maria and Derringer, Jaime and Furlotte, Nicholas A and Galesloot, Tessel E and Girotto, Giorgia and Gupta, Richa and Hall, Leanne M and Harris, Sarah E and Hofer, Edith and Horikoshi, Momoko and Huffman, Jennifer E and Kaasik, Kadri and Kalafati, Ioanna P and Karlsson, Robert and Kong, Augustine and Lahti, Jari and van der Lee, Sven J and deLeeuw, Christiaan and Lind, Penelope A and Lindgren, Karl-Oskar and Liu, Tian and Mangino, Massimo and Marten, Jonathan and Mihailov, Evelin and Miller, Michael B and van der Most, Peter J and Oldmeadow, Christopher and Payton, Antony and Pervjakova, Natalia and Peyrot, Wouter J and Qian, Yong and Raitakari, Olli and Rueedi, Rico and Salvi, Erika and Schmidt, B{\"o}rge and Schraut, Katharina E and Shi, Jianxin and Smith, Albert V and Poot, Raymond A and St Pourcain, Beate and Teumer, Alexander and Thorleifsson, Gudmar and Verweij, Niek and Vuckovic, Dragana and Wellmann, Juergen and Westra, Harm-Jan and Yang, Jingyun and Zhao, Wei and Zhu, Zhihong and Alizadeh, Behrooz Z and Amin, Najaf and Bakshi, Andrew and Baumeister, Sebastian E and Biino, Ginevra and B{\o}nnelykke, Klaus and Boyle, Patricia A and Campbell, Harry and Cappuccio, Francesco P and Davies, Gail and De Neve, Jan-Emmanuel and Deloukas, Panos and Demuth, Ilja and Ding, Jun and Eibich, Peter and Eisele, Lewin and Eklund, Niina and Evans, David M and Faul, Jessica D and Feitosa, Mary F and Forstner, Andreas J and Gandin, Ilaria and Gunnarsson, Bjarni and Halld{\'o}rsson, Bjarni V and Harris, Tamara B and Heath, Andrew C and Hocking, Lynne J and Holliday, Elizabeth G and Homuth, Georg and Horan, Michael A and Hottenga, Jouke-Jan and de Jager, Philip L and Joshi, Peter K and Jugessur, Astanand and Kaakinen, Marika A and K{\"a}h{\"o}nen, Mika and Kanoni, Stavroula and Keltigangas-J{\"a}rvinen, Liisa and Kiemeney, Lambertus A L M and Kolcic, Ivana and Koskinen, Seppo and Kraja, Aldi T and Kroh, Martin and Kutalik, Zolt{\'a}n and Latvala, Antti and Launer, Lenore J and Lebreton, Ma{\"e}l P and Levinson, Douglas F and Lichtenstein, Paul and Lichtner, Peter and Liewald, David C M and Loukola, Anu and Madden, Pamela A and M{\"a}gi, Reedik and M{\"a}ki-Opas, Tomi and Marioni, Riccardo E and Marques-Vidal, Pedro and Meddens, Gerardus A and McMahon, George and Meisinger, Christa and Meitinger, Thomas and Milaneschi, Yusplitri and Milani, Lili and Montgomery, Grant W and Myhre, Ronny and Nelson, Christopher P and Nyholt, Dale R and Ollier, William E R and Palotie, Aarno and Paternoster, Lavinia and Pedersen, Nancy L and Petrovic, Katja E and Porteous, David J and R{\"a}ikk{\"o}nen, Katri and Ring, Susan M and Robino, Antonietta and Rostapshova, Olga and Rudan, Igor and Rustichini, Aldo and Salomaa, Veikko and Sanders, Alan R and Sarin, Antti-Pekka and Schmidt, Helena and Scott, Rodney J and Smith, Blair H and Smith, Jennifer A and Staessen, Jan A and Steinhagen-Thiessen, Elisabeth and Strauch, Konstantin and Terracciano, Antonio and Tobin, Martin D and Ulivi, Sheila and Vaccargiu, Simona and Quaye, Lydia and van Rooij, Frank J A and Venturini, Cristina and Vinkhuyzen, Anna A E and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Vonk, Judith M and Vozzi, Diego and Waage, Johannes and Ware, Erin B and Willemsen, Gonneke and Attia, John R and Bennett, David A and Berger, Klaus and Bertram, Lars and Bisgaard, Hans and Boomsma, Dorret I and Borecki, Ingrid B and B{\"u}ltmann, Ute and Chabris, Christopher F and Cucca, Francesco and Cusi, Daniele and Deary, Ian J and Dedoussis, George V and van Duijn, Cornelia M and Eriksson, Johan G and Franke, Barbara and Franke, Lude and Gasparini, Paolo and Gejman, Pablo V and Gieger, Christian and Grabe, Hans-J{\"o}rgen and Gratten, Jacob and Groenen, Patrick J F and Gudnason, Vilmundur and van der Harst, Pim and Hayward, Caroline and Hinds, David A and Hoffmann, Wolfgang and Hypp{\"o}nen, Elina and Iacono, William G and Jacobsson, Bo and J{\"a}rvelin, Marjo-Riitta and J{\"o}ckel, Karl-Heinz and Kaprio, Jaakko and Kardia, Sharon L R and Lehtim{\"a}ki, Terho and Lehrer, Steven F and Magnusson, Patrik K E and Martin, Nicholas G and McGue, Matt and Metspalu, Andres and Pendleton, Neil and Penninx, Brenda W J H and Perola, Markus and Pirastu, Nicola and Pirastu, Mario and Polasek, Ozren and Posthuma, Danielle and Power, Christine and Province, Michael A and Samani, Nilesh J and Schlessinger, David and Schmidt, Reinhold and S{\o}rensen, Thorkild I A and Spector, Tim D and Stefansson, Kari and Thorsteinsdottir, Unnur and Thurik, A Roy and Timpson, Nicholas J and Tiemeier, Henning and Tung, Joyce Y and Uitterlinden, Andr{\'e} G and Vitart, Veronique and Vollenweider, Peter and Weir, David R and Wilson, James F and Wright, Alan F and Conley, Dalton C and Krueger, Robert F and Davey Smith, George and Hofman, Albert and Laibson, David I and Medland, Sarah E and Meyer, Michelle N and Yang, Jian and Johannesson, Magnus and Visscher, Peter M and Esko, T{\~o}nu and Koellinger, Philipp D and Cesarini, David and Benjamin, Daniel J} } @article {7775, title = {Analysis of functional variants reveals new candidate genes associated with alexithymia.}, journal = {Psychiatry Res}, volume = {227}, year = {2015}, month = {2015 Jun 30}, pages = {363-5}, abstract = {

In this study we explored the possible association between 36,915 functional variants and alexithymia, a personality trait characterized by the inability to identify and describe emotions and feelings. From our analysis, variants in the genes ABCB4, TP53AIP1, ARHGAP32 and TMEM88B were identified linked to the alexithymia phenotype.

}, keywords = {Adolescent, Adult, Affective Symptoms, Aged, Case-Control Studies, DNA-Binding Proteins, Emotions, Female, Humans, Male, Membrane Proteins, Middle Aged, P-Glycoproteins, Personality Inventory, Phenotype, Tumor Suppressor Proteins, Young Adult}, issn = {1872-7123}, doi = {10.1016/j.psychres.2015.03.018}, author = {Mezzavilla, Massimo and Ulivi, Sheila and Bianca, Martina La and Carlino, Davide and Gasparini, Paolo and Robino, Antonietta} } @article {8070, title = {Brain-derived neurotrophic factor serum levels in genetically isolated populations: gender-specific association with anxiety disorder subtypes but not with anxiety levels or Val66Met polymorphism.}, journal = {PeerJ}, volume = {3}, year = {2015}, month = {2015}, pages = {e1252}, abstract = {

Anxiety disorders (ADs) are disabling chronic disorders with exaggerated behavioral response to threats. This study was aimed at testing the hypothesis that ADs may be associated with reduced neurotrophic activity, particularly of Brain-derived neurotrophic factor (BDNF), and determining possible effects of genetics on serum BDNF concentrations. In 672 adult subjects from six isolated villages in North-Eastern Italy with high inbreeding, we determined serum BDNF levels and identified subjects with different ADs subtypes such as Social and Specific Phobias (PHSOC, PHSP), Generalized Anxiety Disorder (GAD), and Panic Disorder (PAD). Analysis of the population as a whole or individual village showed no significant correlation between serum BDNF levels and Val66Met polymorphism and no association with anxiety levels. Stratification of subjects highlighted a significant decrease in serum BDNF in females with GAD and males with PHSP. This study indicates low heritability and absence of any impact of the Val66Met polymorphism on circulating concentrations of BDNF. Our results show that BDNF is not a general biomarker of anxiety but serum BDNF levels correlate in a gender-specific manner with ADs subtypes.

}, issn = {2167-8359}, doi = {10.7717/peerj.1252}, author = {Carlino, Davide and Francavilla, Ruggiero and Baj, Gabriele and Kulak, Karolina and d{\textquoteright}Adamo, Pio and Ulivi, Sheila and Cappellani, Stefania and Gasparini, Paolo and Tongiorgi, Enrico} } @article {7696, title = {Directional dominance on stature and cognition in~diverse human populations.}, journal = {Nature}, volume = {523}, year = {2015}, month = {2015 Jul 23}, pages = {459-62}, abstract = {

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs~of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 {\texttimes} 10(-300), 2.1 {\texttimes} 10(-6), 2.5 {\texttimes} 10(-10) and 1.8 {\texttimes} 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months{\textquoteright} less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

}, keywords = {Biological Evolution, Blood Pressure, Body Height, Cholesterol, LDL, Cognition, Cohort Studies, Educational Status, Female, Forced Expiratory Volume, Genome, Human, Homozygote, Humans, Lung Volume Measurements, Male, Phenotype}, issn = {1476-4687}, doi = {10.1038/nature14618}, author = {Joshi, Peter K and Esko, T{\~o}nu and Mattsson, Hannele and Eklund, Niina and Gandin, Ilaria and Nutile, Teresa and Jackson, Anne U and Schurmann, Claudia and Smith, Albert V and Zhang, Weihua and Okada, Yukinori and Stan{\v c}{\'a}kov{\'a}, Alena and Faul, Jessica D and Zhao, Wei and Bartz, Traci M and Concas, Maria Pina and Franceschini, Nora and Enroth, Stefan and Vitart, Veronique and Trompet, Stella and Guo, Xiuqing and Chasman, Daniel I and O{\textquoteright}Connel, Jeffrey R and Corre, Tanguy and Nongmaithem, Suraj S and Chen, Yuning and Mangino, Massimo and Ruggiero, Daniela and Traglia, Michela and Farmaki, Aliki-Eleni and Kacprowski, Tim and Bjonnes, Andrew and van der Spek, Ashley and Wu, Ying and Giri, Anil K and Yanek, Lisa R and Wang, Lihua and Hofer, Edith and Rietveld, Cornelius A and McLeod, Olga and Cornelis, Marilyn C and Pattaro, Cristian and Verweij, Niek and Baumbach, Clemens and Abdellaoui, Abdel and Warren, Helen R and Vuckovic, Dragana and Mei, Hao and Bouchard, Claude and Perry, John R B and Cappellani, Stefania and Mirza, Saira S and Benton, Miles C and Broeckel, Ulrich and Medland, Sarah E and Lind, Penelope A and Malerba, Giovanni and Drong, Alexander and Yengo, Loic and Bielak, Lawrence F and Zhi, Degui and van der Most, Peter J and Shriner, Daniel and M{\"a}gi, Reedik and Hemani, Gibran and Karaderi, Tugce and Wang, Zhaoming and Liu, Tian and Demuth, Ilja and Zhao, Jing Hua and Meng, Weihua and Lataniotis, Lazaros and van der Laan, Sander W and Bradfield, Jonathan P and Wood, Andrew R and Bonnefond, Amelie and Ahluwalia, Tarunveer S and Hall, Leanne M and Salvi, Erika and Yazar, Seyhan and Carstensen, Lisbeth and de Haan, Hugoline G and Abney, Mark and Afzal, Uzma and Allison, Matthew A and Amin, Najaf and Asselbergs, Folkert W and Bakker, Stephan J L and Barr, R Graham and Baumeister, Sebastian E and Benjamin, Daniel J and Bergmann, Sven and Boerwinkle, Eric and Bottinger, Erwin P and Campbell, Archie and Chakravarti, Aravinda and Chan, Yingleong and Chanock, Stephen J and Chen, Constance and Chen, Y-D Ida and Collins, Francis S and Connell, John and Correa, Adolfo and Cupples, L Adrienne and Smith, George Davey and Davies, Gail and D{\"o}rr, Marcus and Ehret, Georg and Ellis, Stephen B and Feenstra, Bjarke and Feitosa, Mary F and Ford, Ian and Fox, Caroline S and Frayling, Timothy M and Friedrich, Nele and Geller, Frank and Scotland, Generation and Gillham-Nasenya, Irina and Gottesman, Omri and Graff, Misa and Grodstein, Francine and Gu, Charles and Haley, Chris and Hammond, Christopher J and Harris, Sarah E and Harris, Tamara B and Hastie, Nicholas D and Heard-Costa, Nancy L and Heikkil{\"a}, Kauko and Hocking, Lynne J and Homuth, Georg and Hottenga, Jouke-Jan and Huang, Jinyan and Huffman, Jennifer E and Hysi, Pirro G and Ikram, M Arfan and Ingelsson, Erik and Joensuu, Anni and Johansson, {\r A}sa and Jousilahti, Pekka and Jukema, J Wouter and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kanoni, Stavroula and Kerr, Shona M and Khan, Nazir M and Koellinger, Philipp and Koistinen, Heikki A and Kooner, Manraj K and Kubo, Michiaki and Kuusisto, Johanna and Lahti, Jari and Launer, Lenore J and Lea, Rodney A and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Liewald, David C M and Lind, Lars and Loh, Marie and Lokki, Marja-Liisa and London, Stephanie J and Loomis, Stephanie J and Loukola, Anu and Lu, Yingchang and Lumley, Thomas and Lundqvist, Annamari and M{\"a}nnist{\"o}, Satu and Marques-Vidal, Pedro and Masciullo, Corrado and Matchan, Angela and Mathias, Rasika A and Matsuda, Koichi and Meigs, James B and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Mentch, Frank D and Mihailov, Evelin and Milani, Lili and Montasser, May E and Montgomery, Grant W and Morrison, Alanna and Myers, Richard H and Nadukuru, Rajiv and Navarro, Pau and Nelis, Mari and Nieminen, Markku S and Nolte, Ilja M and O{\textquoteright}Connor, George T and Ogunniyi, Adesola and Padmanabhan, Sandosh and Palmas, Walter R and Pankow, James S and Patarcic, Inga and Pavani, Francesca and Peyser, Patricia A and Pietilainen, Kirsi and Poulter, Neil and Prokopenko, Inga and Ralhan, Sarju and Redmond, Paul and Rich, Stephen S and Rissanen, Harri and Robino, Antonietta and Rose, Lynda M and Rose, Richard and Sala, Cinzia and Salako, Babatunde and Salomaa, Veikko and Sarin, Antti-Pekka and Saxena, Richa and Schmidt, Helena and Scott, Laura J and Scott, William R and Sennblad, Bengt and Seshadri, Sudha and Sever, Peter and Shrestha, Smeeta and Smith, Blair H and Smith, Jennifer A and Soranzo, Nicole and Sotoodehnia, Nona and Southam, Lorraine and Stanton, Alice V and Stathopoulou, Maria G and Strauch, Konstantin and Strawbridge, Rona J and Suderman, Matthew J and Tandon, Nikhil and Tang, Sian-Tsun and Taylor, Kent D and Tayo, Bamidele O and T{\"o}glhofer, Anna Maria and Tomaszewski, Maciej and T{\v s}ernikova, Natalia and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and van Hylckama Vlieg, Astrid and van Setten, Jessica and Vasankari, Tuula and Vedantam, Sailaja and Vlachopoulou, Efthymia and Vozzi, Diego and Vuoksimaa, Eero and Waldenberger, Melanie and Ware, Erin B and Wentworth-Shields, William and Whitfield, John B and Wild, Sarah and Willemsen, Gonneke and Yajnik, Chittaranjan S and Yao, Jie and Zaza, Gianluigi and Zhu, Xiaofeng and Salem, Rany M and Melbye, Mads and Bisgaard, Hans and Samani, Nilesh J and Cusi, Daniele and Mackey, David A and Cooper, Richard S and Froguel, Philippe and Pasterkamp, Gerard and Grant, Struan F A and Hakonarson, Hakon and Ferrucci, Luigi and Scott, Robert A and Morris, Andrew D and Palmer, Colin N A and Dedoussis, George and Deloukas, Panos and Bertram, Lars and Lindenberger, Ulman and Berndt, Sonja I and Lindgren, Cecilia M and Timpson, Nicholas J and T{\"o}njes, Anke and Munroe, Patricia B and S{\o}rensen, Thorkild I A and Rotimi, Charles N and Arnett, Donna K and Oldehinkel, Albertine J and Kardia, Sharon L R and Balkau, Beverley and Gambaro, Giovanni and Morris, Andrew P and Eriksson, Johan G and Wright, Margie J and Martin, Nicholas G and Hunt, Steven C and Starr, John M and Deary, Ian J and Griffiths, Lyn R and Tiemeier, Henning and Pirastu, Nicola and Kaprio, Jaakko and Wareham, Nicholas J and P{\'e}russe, Louis and Wilson, James G and Girotto, Giorgia and Caulfield, Mark J and Raitakari, Olli and Boomsma, Dorret I and Gieger, Christian and van der Harst, Pim and Hicks, Andrew A and Kraft, Peter and Sinisalo, Juha and Knekt, Paul and Johannesson, Magnus and Magnusson, Patrik K E and Hamsten, Anders and Schmidt, Reinhold and Borecki, Ingrid B and Vartiainen, Erkki and Becker, Diane M and Bharadwaj, Dwaipayan and Mohlke, Karen L and Boehnke, Michael and van Duijn, Cornelia M and Sanghera, Dharambir K and Teumer, Alexander and Zeggini, Eleftheria and Metspalu, Andres and Gasparini, Paolo and Ulivi, Sheila and Ober, Carole and Toniolo, Daniela and Rudan, Igor and Porteous, David J and Ciullo, Marina and Spector, Tim D and Hayward, Caroline and Dupuis, Jos{\'e}e and Loos, Ruth J F and Wright, Alan F and Chandak, Giriraj R and Vollenweider, Peter and Shuldiner, Alan R and Ridker, Paul M and Rotter, Jerome I and Sattar, Naveed and Gyllensten, Ulf and North, Kari E and Pirastu, Mario and Psaty, Bruce M and Weir, David R and Laakso, Markku and Gudnason, Vilmundur and Takahashi, Atsushi and Chambers, John C and Kooner, Jaspal S and Strachan, David P and Campbell, Harry and Hirschhorn, Joel N and Perola, Markus and Polasek, Ozren and Wilson, James F} } @article {8066, title = {Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Nov}, pages = {1294-303}, abstract = {

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in \~{}70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (\~{}6\% increase in risk per year; P = 3 {\texttimes} 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

}, issn = {1546-1718}, doi = {10.1038/ng.3412}, author = {Day, Felix R and Ruth, Katherine S and Thompson, Deborah J and Lunetta, Kathryn L and Pervjakova, Natalia and Chasman, Daniel I and Stolk, Lisette and Finucane, Hilary K and Sulem, Patrick and Bulik-Sullivan, Brendan and Esko, T{\~o}nu and Johnson, Andrew D and Elks, Cathy E and Franceschini, Nora and He, Chunyan and Altmaier, Elisabeth and Brody, Jennifer A and Franke, Lude L and Huffman, Jennifer E and Keller, Margaux F and McArdle, Patrick F and Nutile, Teresa and Porcu, Eleonora and Robino, Antonietta and Rose, Lynda M and Schick, Ursula M and Smith, Jennifer A and Teumer, Alexander and Traglia, Michela and Vuckovic, Dragana and Yao, Jie and Zhao, Wei and Albrecht, Eva and Amin, Najaf and Corre, Tanguy and Hottenga, Jouke-Jan and Mangino, Massimo and Smith, Albert V and Tanaka, Toshiko and Abecasis, Goncalo R and Andrulis, Irene L and Anton-Culver, Hoda and Antoniou, Antonis C and Arndt, Volker and Arnold, Alice M and Barbieri, Caterina and Beckmann, Matthias W and Beeghly-Fadiel, Alicia and Benitez, Javier and Bernstein, Leslie and Bielinski, Suzette J and Blomqvist, Carl and Boerwinkle, Eric and Bogdanova, Natalia V and Bojesen, Stig E and Bolla, Manjeet K and Borresen-Dale, Anne-Lise and Boutin, Thibaud S and Brauch, Hiltrud and Brenner, Hermann and Br{\"u}ning, Thomas and Burwinkel, Barbara and Campbell, Archie and Campbell, Harry and Chanock, Stephen J and Chapman, J Ross and Chen, Yii-Der Ida and Chenevix-Trench, Georgia and Couch, Fergus J and Coviello, Andrea D and Cox, Angela and Czene, Kamila and Darabi, Hatef and De Vivo, Immaculata and Demerath, Ellen W and Dennis, Joe and Devilee, Peter and D{\"o}rk, Thilo and Dos-Santos-Silva, Isabel and Dunning, Alison M and Eicher, John D and Fasching, Peter A and Faul, Jessica D and Figueroa, Jonine and Flesch-Janys, Dieter and Gandin, Ilaria and Garcia, Melissa E and Garc{\'\i}a-Closas, Montserrat and Giles, Graham G and Girotto, Giorgia G and Goldberg, Mark S and Gonz{\'a}lez-Neira, Anna and Goodarzi, Mark O and Grove, Megan L and Gudbjartsson, Daniel F and Guenel, Pascal and Guo, Xiuqing and Haiman, Christopher A and Hall, Per and Hamann, Ute and Henderson, Brian E and Hocking, Lynne J and Hofman, Albert and Homuth, Georg and Hooning, Maartje J and Hopper, John L and Hu, Frank B and Huang, Jinyan and Humphreys, Keith and Hunter, David J and Jakubowska, Anna and Jones, Samuel E and Kabisch, Maria and Karasik, David and Knight, Julia A and Kolcic, Ivana and Kooperberg, Charles and Kosma, Veli-Matti and Kriebel, Jennifer and Kristensen, Vessela and Lambrechts, Diether and Langenberg, Claudia and Li, Jingmei and Li, Xin and Lindstr{\"o}m, Sara and Liu, Yongmei and Luan, Jian{\textquoteright}an and Lubinski, Jan and M{\"a}gi, Reedik and Mannermaa, Arto and Manz, Judith and Margolin, Sara and Marten, Jonathan and Martin, Nicholas G and Masciullo, Corrado and Meindl, Alfons and Michailidou, Kyriaki and Mihailov, Evelin and Milani, Lili and Milne, Roger L and M{\"u}ller-Nurasyid, Martina and Nalls, Michael and Neale, Benjamin M and Nevanlinna, Heli and Neven, Patrick and Newman, Anne B and Nordestgaard, B{\o}rge G and Olson, Janet E and Padmanabhan, Sandosh and Peterlongo, Paolo and Peters, Ulrike and Petersmann, Astrid and Peto, Julian and Pharoah, Paul D P and Pirastu, Nicola N and Pirie, Ailith and Pistis, Giorgio and Polasek, Ozren and Porteous, David and Psaty, Bruce M and Pylk{\"a}s, Katri and Radice, Paolo and Raffel, Leslie J and Rivadeneira, Fernando and Rudan, Igor and Rudolph, Anja and Ruggiero, Daniela and Sala, Cinzia F and Sanna, Serena and Sawyer, Elinor J and Schlessinger, David and Schmidt, Marjanka K and Schmidt, Frank and Schmutzler, Rita K and Schoemaker, Minouk J and Scott, Robert A and Seynaeve, Caroline M and Simard, Jacques and Sorice, Rossella and Southey, Melissa C and St{\"o}ckl, Doris and Strauch, Konstantin and Swerdlow, Anthony and Taylor, Kent D and Thorsteinsdottir, Unnur and Toland, Amanda E and Tomlinson, Ian and Truong, Therese and Tryggvadottir, Laufey and Turner, Stephen T and Vozzi, Diego and Wang, Qin and Wellons, Melissa and Willemsen, Gonneke and Wilson, James F and Winqvist, Robert and Wolffenbuttel, Bruce B H R and Wright, Alan F and Yannoukakos, Drakoulis and Zemunik, Tatijana and Zheng, Wei and Zygmunt, Marek and Bergmann, Sven and Boomsma, Dorret I and Buring, Julie E and Ferrucci, Luigi and Montgomery, Grant W and Gudnason, Vilmundur and Spector, Tim D and van Duijn, Cornelia M and Alizadeh, Behrooz Z and Ciullo, Marina and Crisponi, Laura and Easton, Douglas F and Gasparini, Paolo P and Gieger, Christian and Harris, Tamara B and Hayward, Caroline and Kardia, Sharon L R and Kraft, Peter and McKnight, Barbara and Metspalu, Andres and Morrison, Alanna C and Reiner, Alex P and Ridker, Paul M and Rotter, Jerome I and Toniolo, Daniela and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and V{\"o}lzke, Henry and Wareham, Nicholas J and Weir, David R and Yerges-Armstrong, Laura M and Price, Alkes L and Stefansson, Kari and Visser, Jenny A and Ong, Ken K and Chang-Claude, Jenny and Murabito, Joanne M and Perry, John R B and Murray, Anna} } @article {7784, title = {Modulation of genetic associations with serum urate levels by body-mass-index in humans.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0119752}, abstract = {

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95\% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0119752}, author = {Huffman, Jennifer E and Albrecht, Eva and Teumer, Alexander and Mangino, Massimo and Kapur, Karen and Johnson, Toby and Kutalik, Zolt{\'a}n and Pirastu, Nicola and Pistis, Giorgio and Lopez, Lorna M and Haller, Toomas and Salo, Perttu and Goel, Anuj and Li, Man and Tanaka, Toshiko and Dehghan, Abbas and Ruggiero, Daniela and Malerba, Giovanni and Smith, Albert V and Nolte, Ilja M and Portas, Laura and Phipps-Green, Amanda and Boteva, Lora and Navarro, Pau and Johansson, {\r A}sa and Hicks, Andrew A and Polasek, Ozren and Esko, T{\~o}nu and Peden, John F and Harris, Sarah E and Murgia, Federico and Wild, Sarah H and Tenesa, Albert and Tin, Adrienne and Mihailov, Evelin and Grotevendt, Anne and Gislason, Gauti K and Coresh, Josef and d{\textquoteright}Adamo, Pio and Ulivi, Sheila and Vollenweider, Peter and Waeber, Gerard and Campbell, Susan and Kolcic, Ivana and Fisher, Krista and Viigimaa, Margus and Metter, Jeffrey E and Masciullo, Corrado and Trabetti, Elisabetta and Bombieri, Cristina and Sorice, Rossella and D{\"o}ring, Angela and Reischl, Eva and Strauch, Konstantin and Hofman, Albert and Uitterlinden, Andr{\'e} G and Waldenberger, Melanie and Wichmann, H-Erich and Davies, Gail and Gow, Alan J and Dalbeth, Nicola and Stamp, Lisa and Smit, Johannes H and Kirin, Mirna and Nagaraja, Ramaiah and Nauck, Matthias and Schurmann, Claudia and Budde, Kathrin and Farrington, Susan M and Theodoratou, Evropi and Jula, Antti and Salomaa, Veikko and Sala, Cinzia and Hengstenberg, Christian and Burnier, Michel and M{\"a}gi, Reedik and Klopp, Norman and Kloiber, Stefan and Schipf, Sabine and Ripatti, Samuli and Cabras, Stefano and Soranzo, Nicole and Homuth, Georg and Nutile, Teresa and Munroe, Patricia B and Hastie, Nicholas and Campbell, Harry and Rudan, Igor and Cabrera, Claudia and Haley, Chris and Franco, Oscar H and Merriman, Tony R and Gudnason, Vilmundur and Pirastu, Mario and Penninx, Brenda W and Snieder, Harold and Metspalu, Andres and Ciullo, Marina and Pramstaller, Peter P and van Duijn, Cornelia M and Ferrucci, Luigi and Gambaro, Giovanni and Deary, Ian J and Dunlop, Malcolm G and Wilson, James F and Gasparini, Paolo and Gyllensten, Ulf and Spector, Tim D and Wright, Alan F and Hayward, Caroline and Watkins, Hugh and Perola, Markus and Bochud, Murielle and Kao, W H Linda and Caulfield, Mark and Toniolo, Daniela and V{\"o}lzke, Henry and Gieger, Christian and K{\"o}ttgen, Anna and Vitart, Veronique} } @article {7736, title = {Rare coding variants and X-linked loci associated with age at menarche.}, journal = {Nat Commun}, volume = {6}, year = {2015}, month = {2015}, pages = {7756}, abstract = {

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only \~{}3\% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6\%; effect sizes 0.08-1.25 years per allele; P<5 {\texttimes} 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 {\texttimes} 10(-13)) and FAAH2 (rs5914101, P=4.9 {\texttimes} 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 {\texttimes} 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain \~{}0.5\% variance, indicating that these overlooked sources of variation do not substantially explain the {\textquoteright}missing heritability{\textquoteright} of this complex trait.

}, issn = {2041-1723}, doi = {10.1038/ncomms8756}, author = {Lunetta, Kathryn L and Day, Felix R and Sulem, Patrick and Ruth, Katherine S and Tung, Joyce Y and Hinds, David A and Esko, T{\~o}nu and Elks, Cathy E and Altmaier, Elisabeth and He, Chunyan and Huffman, Jennifer E and Mihailov, Evelin and Porcu, Eleonora and Robino, Antonietta and Rose, Lynda M and Schick, Ursula M and Stolk, Lisette and Teumer, Alexander and Thompson, Deborah J and Traglia, Michela and Wang, Carol A and Yerges-Armstrong, Laura M and Antoniou, Antonis C and Barbieri, Caterina and Coviello, Andrea D and Cucca, Francesco and Demerath, Ellen W and Dunning, Alison M and Gandin, Ilaria and Grove, Megan L and Gudbjartsson, Daniel F and Hocking, Lynne J and Hofman, Albert and Huang, Jinyan and Jackson, Rebecca D and Karasik, David and Kriebel, Jennifer and Lange, Ethan M and Lange, Leslie A and Langenberg, Claudia and Li, Xin and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Morrison, Alanna C and Padmanabhan, Sandosh and Pirie, Ailith and Polasek, Ozren and Porteous, David and Reiner, Alex P and Rivadeneira, Fernando and Rudan, Igor and Sala, Cinzia F and Schlessinger, David and Scott, Robert A and St{\"o}ckl, Doris and Visser, Jenny A and V{\"o}lker, Uwe and Vozzi, Diego and Wilson, James G and Zygmunt, Marek and Boerwinkle, Eric and Buring, Julie E and Crisponi, Laura and Easton, Douglas F and Hayward, Caroline and Hu, Frank B and Liu, Simin and Metspalu, Andres and Pennell, Craig E and Ridker, Paul M and Strauch, Konstantin and Streeten, Elizabeth A and Toniolo, Daniela and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and V{\"o}lzke, Henry and Wareham, Nicholas J and Wellons, Melissa and Franceschini, Nora and Chasman, Daniel I and Thorsteinsdottir, Unnur and Murray, Anna and Stefansson, Kari and Murabito, Joanne M and Ong, Ken K and Perry, John R B} } @article {3506, title = {Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis.}, journal = {J Am Soc Nephrol}, volume = {25}, year = {2014}, month = {2014 Aug}, pages = {1869-82}, abstract = {

Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 μg/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function.

}, keywords = {Creatinine, European Continental Ancestry Group, Genetic Variation, Humans, Polymorphism, Single Nucleotide, Uromodulin}, issn = {1533-3450}, doi = {10.1681/ASN.2013070781}, author = {Olden, Matthias and Corre, Tanguy and Hayward, Caroline and Toniolo, Daniela and Ulivi, Sheila and Gasparini, Paolo and Pistis, Giorgio and Hwang, Shih-Jen and Bergmann, Sven and Campbell, Harry and Cocca, Massimiliano and Gandin, Ilaria and Girotto, Giorgia and Glaudemans, Bob and Hastie, Nicholas D and Loffing, Johannes and Polasek, Ozren and Rampoldi, Luca and Rudan, Igor and Sala, Cinzia and Traglia, Michela and Vollenweider, Peter and Vuckovic, Dragana and Youhanna, Sonia and Weber, Julien and Wright, Alan F and Kutalik, Zolt{\'a}n and Bochud, Murielle and Fox, Caroline S and Devuyst, Olivier} } @article {3480, title = {DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 May 1}, pages = {2490-7}, abstract = {

The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to \~{}50\% of the variation in both age at menarche and menopause, but to date the known genes explain <15\% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 {\texttimes} 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.

}, keywords = {Age Factors, DNA-Binding Proteins, Female, Genome-Wide Association Study, Humans, Menopause, Polymorphism, Single Nucleotide}, issn = {1460-2083}, doi = {10.1093/hmg/ddt620}, author = {Perry, John R B and Hsu, Yi-Hsiang and Chasman, Daniel I and Johnson, Andrew D and Elks, Cathy and Albrecht, Eva and Andrulis, Irene L and Beesley, Jonathan and Berenson, Gerald S and Bergmann, Sven and Bojesen, Stig E and Bolla, Manjeet K and Brown, Judith and Buring, Julie E and Campbell, Harry and Chang-Claude, Jenny and Chenevix-Trench, Georgia and Corre, Tanguy and Couch, Fergus J and Cox, Angela and Czene, Kamila and d{\textquoteright}Adamo, Adamo Pio and Davies, Gail and Deary, Ian J and Dennis, Joe and Easton, Douglas F and Engelhardt, Ellen G and Eriksson, Johan G and Esko, T{\~o}nu and Fasching, Peter A and Figueroa, Jonine D and Flyger, Henrik and Fraser, Abigail and Garcia-Closas, Montse and Gasparini, Paolo and Gieger, Christian and Giles, Graham and Guenel, Pascal and H{\"a}gg, Sara and Hall, Per and Hayward, Caroline and Hopper, John and Ingelsson, Erik and Kardia, Sharon L R and Kasiman, Katherine and Knight, Julia A and Lahti, Jari and Lawlor, Debbie A and Magnusson, Patrik K E and Margolin, Sara and Marsh, Julie A and Metspalu, Andres and Olson, Janet E and Pennell, Craig E and Polasek, Ozren and Rahman, Iffat and Ridker, Paul M and Robino, Antonietta and Rudan, Igor and Rudolph, Anja and Salumets, Andres and Schmidt, Marjanka K and Schoemaker, Minouk J and Smith, Erin N and Smith, Jennifer A and Southey, Melissa and St{\"o}ckl, Doris and Swerdlow, Anthony J and Thompson, Deborah J and Truong, Therese and Ulivi, Sheila and Waldenberger, Melanie and Wang, Qin and Wild, Sarah and Wilson, James F and Wright, Alan F and Zgaga, Lina and Ong, Ken K and Murabito, Joanne M and Karasik, David and Murray, Anna} } @article {3520, title = {A general approach for haplotype phasing across the full spectrum of relatedness.}, journal = {PLoS Genet}, volume = {10}, year = {2014}, month = {2014 Apr}, pages = {e1004234}, abstract = {

Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally {\textquoteright}unrelated{\textquoteright} individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.

}, keywords = {Chromosome Mapping, Cohort Effect, Family, Genotype, Haplotypes, Humans, Models, Genetic, Pedigree, Phenotype, Recombination, Genetic}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004234}, author = {O{\textquoteright}Connell, Jared and Gurdasani, Deepti and Delaneau, Olivier and Pirastu, Nicola and Ulivi, Sheila and Cocca, Massimiliano and Traglia, Michela and Huang, Jie and Huffman, Jennifer E and Rudan, Igor and McQuillan, Ruth and Fraser, Ross M and Campbell, Harry and Polasek, Ozren and Asiki, Gershim and Ekoru, Kenneth and Hayward, Caroline and Wright, Alan F and Vitart, Veronique and Navarro, Pau and Zagury, Jean-Francois and Wilson, James F and Toniolo, Daniela and Gasparini, Paolo and Soranzo, Nicole and Sandhu, Manjinder S and Marchini, Jonathan} } @article {3568, title = {Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Aug}, pages = {826-36}, abstract = {

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain \~{}8-10\% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

}, keywords = {Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Male, Middle Aged, Myocardium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.3014}, author = {Arking, Dan E and Pulit, Sara L and Crotti, Lia and van der Harst, Pim and Munroe, Patricia B and Koopmann, Tamara T and Sotoodehnia, Nona and Rossin, Elizabeth J and Morley, Michael and Wang, Xinchen and Johnson, Andrew D and Lundby, Alicia and Gudbjartsson, Daniel F and Noseworthy, Peter A and Eijgelsheim, Mark and Bradford, Yuki and Tarasov, Kirill V and D{\"o}rr, Marcus and M{\"u}ller-Nurasyid, Martina and Lahtinen, Annukka M and Nolte, Ilja M and Smith, Albert Vernon and Bis, Joshua C and Isaacs, Aaron and Newhouse, Stephen J and Evans, Daniel S and Post, Wendy S and Waggott, Daryl and Lyytik{\"a}inen, Leo-Pekka and Hicks, Andrew A and Eisele, Lewin and Ellinghaus, David and Hayward, Caroline and Navarro, Pau and Ulivi, Sheila and Tanaka, Toshiko and Tester, David J and Chatel, St{\'e}phanie and Gustafsson, Stefan and Kumari, Meena and Morris, Richard W and Naluai, {\r A}sa T and Padmanabhan, Sandosh and Kluttig, Alexander and Strohmer, Bernhard and Panayiotou, Andrie G and Torres, Maria and Knoflach, Michael and Hubacek, Jaroslav A and Slowikowski, Kamil and Raychaudhuri, Soumya and Kumar, Runjun D and Harris, Tamara B and Launer, Lenore J and Shuldiner, Alan R and Alonso, Alvaro and Bader, Joel S and Ehret, Georg and Huang, Hailiang and Kao, W H Linda and Strait, James B and Macfarlane, Peter W and Brown, Morris and Caulfield, Mark J and Samani, Nilesh J and Kronenberg, Florian and Willeit, Johann and Smith, J Gustav and Greiser, Karin H and Meyer Zu Schwabedissen, Henriette and Werdan, Karl and Carella, Massimo and Zelante, Leopoldo and Heckbert, Susan R and Psaty, Bruce M and Rotter, Jerome I and Kolcic, Ivana and Polasek, Ozren and Wright, Alan F and Griffin, Maura and Daly, Mark J and Arnar, David O and Holm, Hilma and Thorsteinsdottir, Unnur and Denny, Joshua C and Roden, Dan M and Zuvich, Rebecca L and Emilsson, Valur and Plump, Andrew S and Larson, Martin G and O{\textquoteright}Donnell, Christopher J and Yin, Xiaoyan and Bobbo, Marco and d{\textquoteright}Adamo, Adamo P and Iorio, Annamaria and Sinagra, Gianfranco and Carracedo, Angel and Cummings, Steven R and Nalls, Michael A and Jula, Antti and Kontula, Kimmo K and Marjamaa, Annukka and Oikarinen, Lasse and Perola, Markus and Porthan, Kimmo and Erbel, Raimund and Hoffmann, Per and J{\"o}ckel, Karl-Heinz and K{\"a}lsch, Hagen and N{\"o}then, Markus M and den Hoed, Marcel and Loos, Ruth J F and Thelle, Dag S and Gieger, Christian and Meitinger, Thomas and Perz, Siegfried and Peters, Annette and Prucha, Hanna and Sinner, Moritz F and Waldenberger, Melanie and de Boer, Rudolf A and Franke, Lude and van der Vleuten, Pieter A and Beckmann, Britt Maria and Martens, Eimo and Bardai, Abdennasser and Hofman, Nynke and Wilde, Arthur A M and Behr, Elijah R and Dalageorgou, Chrysoula and Giudicessi, John R and Medeiros-Domingo, Argelia and Barc, Julien and Kyndt, Florence and Probst, Vincent and Ghidoni, Alice and Insolia, Roberto and Hamilton, Robert M and Scherer, Stephen W and Brandimarto, Jeffrey and Margulies, Kenneth and Moravec, Christine E and del Greco M, Fabiola and Fuchsberger, Christian and O{\textquoteright}Connell, Jeffrey R and Lee, Wai K and Watt, Graham C M and Campbell, Harry and Wild, Sarah H and El Mokhtari, Nour E and Frey, Norbert and Asselbergs, Folkert W and Mateo Leach, Irene and Navis, Gerjan and van den Berg, Maarten P and van Veldhuisen, Dirk J and Kellis, Manolis and Krijthe, Bouwe P and Franco, Oscar H and Hofman, Albert and Kors, Jan A and Uitterlinden, Andr{\'e} G and Witteman, Jacqueline C M and Kedenko, Lyudmyla and Lamina, Claudia and Oostra, Ben A and Abecasis, Goncalo R and Lakatta, Edward G and Mulas, Antonella and Orru, Marco and Schlessinger, David and Uda, Manuela and Markus, Marcello R P and V{\"o}lker, Uwe and Snieder, Harold and Spector, Timothy D and Arnl{\"o}v, Johan and Lind, Lars and Sundstr{\"o}m, Johan and Syv{\"a}nen, Ann-Christine and Kivimaki, Mika and K{\"a}h{\"o}nen, Mika and Mononen, Nina and Raitakari, Olli T and Viikari, Jorma S and Adamkova, Vera and Kiechl, Stefan and Brion, Maria and Nicolaides, Andrew N and Paulweber, Bernhard and Haerting, Johannes and Dominiczak, Anna F and Nyberg, Fredrik and Whincup, Peter H and Hingorani, Aroon D and Schott, Jean-Jacques and Bezzina, Connie R and Ingelsson, Erik and Ferrucci, Luigi and Gasparini, Paolo and Wilson, James F and Rudan, Igor and Franke, Andre and M{\"u}hleisen, Thomas W and Pramstaller, Peter P and Lehtim{\"a}ki, Terho J and Paterson, Andrew D and Parsa, Afshin and Liu, Yongmei and van Duijn, Cornelia M and Siscovick, David S and Gudnason, Vilmundur and Jamshidi, Yalda and Salomaa, Veikko and Felix, Stephan B and Sanna, Serena and Ritchie, Marylyn D and Stricker, Bruno H and Stefansson, Kari and Boyer, Laurie A and Cappola, Thomas P and Olsen, Jesper V and Lage, Kasper and Schwartz, Peter J and K{\"a}{\"a}b, Stefan and Chakravarti, Aravinda and Ackerman, Michael J and Pfeufer, Arne and de Bakker, Paul I W and Newton-Cheh, Christopher} } @article {3512, title = {Insight into genetic determinants of resting heart rate.}, journal = {Gene}, volume = {545}, year = {2014}, month = {2014 Jul 15}, pages = {170-4}, abstract = {

BACKGROUND: Recent studies suggested that resting heart rate (RHR) might be an independent predictor of cardiovascular mortality and morbidity. Nonetheless, the interrelation between RHR and cardiovascular diseases is not clear. In order to resolve this puzzle, the importance of genetic determinants of RHR has been recently suggested, but it needs to be further investigated.

OBJECTIVE: The aim of this study was to estimate the contribution of common genetic variations on RHR using Genome Wide Association Study.

METHODS: We performed a Genome Wide Association Study in an isolated population cohort of 1737 individuals, the Italian Network on Genetic Isolates - Friuli Venezia Giulia (INGI-FVG). Moreover, a haplotype analysis was performed. A regression tree analysis was run to highlight the effect of each haplotype combination on the phenotype.

RESULTS: A significant level of association (p<5 {\texttimes} 10(-8)) was detected for Single Nucleotide Polymorphisms (SNPs) in two genes expressed in the heart: MAML1 and CANX. Founding that the three different variants of the haplotype, which encompass both genes, yielded a phenotypic correlation. Indeed, a haplotype in homozygosity is significantly associated with the lower quartile of RHR (RHR <= 58 bpm). Moreover no significant association was found between cardiovascular risk factors and the different haplotype combinations.

CONCLUSION: Mastermind-like 1 and Calnexin were found to be associated with RHR. We demonstrated a relation between a haplotype and the lower quartile of RHR in our populations. Our findings highlight that genetic determinants of RHR may be implicated in determining cardiovascular diseases and could allow a better risk stratification.

}, keywords = {Calnexin, Cardiovascular Diseases, DNA-Binding Proteins, Female, Genome-Wide Association Study, Haplotypes, Heart Rate, Humans, Italy, Male, Middle Aged, Polymorphism, Single Nucleotide, Regression Analysis, Transcription Factors}, issn = {1879-0038}, doi = {10.1016/j.gene.2014.03.045}, author = {Mezzavilla, Massimo and Iorio, Annamaria and Bobbo, Marco and D{\textquoteright}Eustacchio, Angela and Merlo, Marco and Gasparini, Paolo and Ulivi, Sheila and Sinagra, Gianfranco} } @article {3593, title = {Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.}, journal = {Nature}, volume = {514}, year = {2014}, month = {2014 Oct 2}, pages = {92-7}, abstract = {

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 {\texttimes} 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

}, keywords = {Adolescent, Age Factors, Alleles, Body Mass Index, Breast Neoplasms, Cardiovascular Diseases, Child, Diabetes Mellitus, Type 2, Europe, Female, Genetic Loci, Genome-Wide Association Study, Genomic Imprinting, Humans, Hypothalamo-Hypophyseal System, Intercellular Signaling Peptides and Proteins, Male, Membrane Proteins, Menarche, Obesity, Ovary, Parents, Polymorphism, Single Nucleotide, Potassium Channels, Tandem Pore Domain, Proteins, Quantitative Trait Loci, Receptors, GABA-B, Receptors, Retinoic Acid, Ribonucleoproteins}, issn = {1476-4687}, doi = {10.1038/nature13545}, author = {Perry, John R B and Day, Felix and Elks, Cathy E and Sulem, Patrick and Thompson, Deborah J and Ferreira, Teresa and He, Chunyan and Chasman, Daniel I and Esko, T{\~o}nu and Thorleifsson, Gudmar and Albrecht, Eva and Ang, Wei Q and Corre, Tanguy and Cousminer, Diana L and Feenstra, Bjarke and Franceschini, Nora and Ganna, Andrea and Johnson, Andrew D and Kjellqvist, Sanela and Lunetta, Kathryn L and McMahon, George and Nolte, Ilja M and Paternoster, Lavinia and Porcu, Eleonora and Smith, Albert V and Stolk, Lisette and Teumer, Alexander and T{\v s}ernikova, Natalia and Tikkanen, Emmi and Ulivi, Sheila and Wagner, Erin K and Amin, Najaf and Bierut, Laura J and Byrne, Enda M and Hottenga, Jouke-Jan and Koller, Daniel L and Mangino, Massimo and Pers, Tune H and Yerges-Armstrong, Laura M and Hua Zhao, Jing and Andrulis, Irene L and Anton-Culver, Hoda and Atsma, Femke and Bandinelli, Stefania and Beckmann, Matthias W and Benitez, Javier and Blomqvist, Carl and Bojesen, Stig E and Bolla, Manjeet K and Bonanni, Bernardo and Brauch, Hiltrud and Brenner, Hermann and Buring, Julie E and Chang-Claude, Jenny and Chanock, Stephen and Chen, Jinhui and Chenevix-Trench, Georgia and Coll{\'e}e, J Margriet and Couch, Fergus J and Couper, David and Coviello, Andrea D and Cox, Angela and Czene, Kamila and d{\textquoteright}Adamo, Adamo Pio and Davey Smith, George and De Vivo, Immaculata and Demerath, Ellen W and Dennis, Joe and Devilee, Peter and Dieffenbach, Aida K and Dunning, Alison M and Eiriksdottir, Gudny and Eriksson, Johan G and Fasching, Peter A and Ferrucci, Luigi and Flesch-Janys, Dieter and Flyger, Henrik and Foroud, Tatiana and Franke, Lude and Garcia, Melissa E and Garc{\'\i}a-Closas, Montserrat and Geller, Frank and de Geus, Eco E J and Giles, Graham G and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Guenel, Pascal and Guo, Suiqun and Hall, Per and Hamann, Ute and Haring, Robin and Hartman, Catharina A and Heath, Andrew C and Hofman, Albert and Hooning, Maartje J and Hopper, John L and Hu, Frank B and Hunter, David J and Karasik, David and Kiel, Douglas P and Knight, Julia A and Kosma, Veli-Matti and Kutalik, Zolt{\'a}n and Lai, Sandra and Lambrechts, Diether and Lindblom, Annika and M{\"a}gi, Reedik and Magnusson, Patrik K and Mannermaa, Arto and Martin, Nicholas G and Masson, Gisli and McArdle, Patrick F and McArdle, Wendy L and Melbye, Mads and Michailidou, Kyriaki and Mihailov, Evelin and Milani, Lili and Milne, Roger L and Nevanlinna, Heli and Neven, Patrick and Nohr, Ellen A and Oldehinkel, Albertine J and Oostra, Ben A and Palotie, Aarno and Peacock, Munro and Pedersen, Nancy L and Peterlongo, Paolo and Peto, Julian and Pharoah, Paul D P and Postma, Dirkje S and Pouta, Anneli and Pylk{\"a}s, Katri and Radice, Paolo and Ring, Susan and Rivadeneira, Fernando and Robino, Antonietta and Rose, Lynda M and Rudolph, Anja and Salomaa, Veikko and Sanna, Serena and Schlessinger, David and Schmidt, Marjanka K and Southey, Mellissa C and Sovio, Ulla and Stampfer, Meir J and St{\"o}ckl, Doris and Storniolo, Anna M and Timpson, Nicholas J and Tyrer, Jonathan and Visser, Jenny A and Vollenweider, Peter and V{\"o}lzke, Henry and Waeber, Gerard and Waldenberger, Melanie and Wallaschofski, Henri and Wang, Qin and Willemsen, Gonneke and Winqvist, Robert and Wolffenbuttel, Bruce H R and Wright, Margaret J and Boomsma, Dorret I and Econs, Michael J and Khaw, Kay-Tee and Loos, Ruth J F and McCarthy, Mark I and Montgomery, Grant W and Rice, John P and Streeten, Elizabeth A and Thorsteinsdottir, Unnur and van Duijn, Cornelia M and Alizadeh, Behrooz Z and Bergmann, Sven and Boerwinkle, Eric and Boyd, Heather A and Crisponi, Laura and Gasparini, Paolo and Gieger, Christian and Harris, Tamara B and Ingelsson, Erik and J{\"a}rvelin, Marjo-Riitta and Kraft, Peter and Lawlor, Debbie and Metspalu, Andres and Pennell, Craig E and Ridker, Paul M and Snieder, Harold and S{\o}rensen, Thorkild I A and Spector, Tim D and Strachan, David P and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Widen, Elisabeth and Zygmunt, Marek and Murray, Anna and Easton, Douglas F and Stefansson, Kari and Murabito, Joanne M and Ong, Ken K} } @article {3474, title = {Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Feb}, pages = {145-54}, abstract = {

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

}, keywords = {Analysis of Variance, European Continental Ancestry Group, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Glucose, Gout, Humans, Inhibins, Polymorphism, Single Nucleotide, Signal Transduction, Uric Acid}, issn = {1546-1718}, doi = {10.1038/ng.2500}, author = {K{\"o}ttgen, Anna and Albrecht, Eva and Teumer, Alexander and Vitart, Veronique and Krumsiek, Jan and Hundertmark, Claudia and Pistis, Giorgio and Ruggiero, Daniela and O{\textquoteright}Seaghdha, Conall M and Haller, Toomas and Yang, Qiong and Tanaka, Toshiko and Johnson, Andrew D and Kutalik, Zolt{\'a}n and Smith, Albert V and Shi, Julia and Struchalin, Maksim and Middelberg, Rita P S and Brown, Morris J and Gaffo, Angelo L and Pirastu, Nicola and Li, Guo and Hayward, Caroline and Zemunik, Tatijana and Huffman, Jennifer and Yengo, Loic and Zhao, Jing Hua and Demirkan, Ayse and Feitosa, Mary F and Liu, Xuan and Malerba, Giovanni and Lopez, Lorna M and van der Harst, Pim and Li, Xinzhong and Kleber, Marcus E and Hicks, Andrew A and Nolte, Ilja M and Johansson, {\r A}sa and Murgia, Federico and Wild, Sarah H and Bakker, Stephan J L and Peden, John F and Dehghan, Abbas and Steri, Maristella and Tenesa, Albert and Lagou, Vasiliki and Salo, Perttu and Mangino, Massimo and Rose, Lynda M and Lehtim{\"a}ki, Terho and Woodward, Owen M and Okada, Yukinori and Tin, Adrienne and M{\"u}ller, Christian and Oldmeadow, Christopher and Putku, Margus and Czamara, Darina and Kraft, Peter and Frogheri, Laura and Thun, Gian Andri and Grotevendt, Anne and Gislason, Gauti Kjartan and Harris, Tamara B and Launer, Lenore J and McArdle, Patrick and Shuldiner, Alan R and Boerwinkle, Eric and Coresh, Josef and Schmidt, Helena and Schallert, Michael and Martin, Nicholas G and Montgomery, Grant W and Kubo, Michiaki and Nakamura, Yusuke and Tanaka, Toshihiro and Munroe, Patricia B and Samani, Nilesh J and Jacobs, David R and Liu, Kiang and d{\textquoteright}Adamo, Pio and Ulivi, Sheila and Rotter, Jerome I and Psaty, Bruce M and Vollenweider, Peter and Waeber, Gerard and Campbell, Susan and Devuyst, Olivier and Navarro, Pau and Kolcic, Ivana and Hastie, Nicholas and Balkau, Beverley and Froguel, Philippe and Esko, T{\~o}nu and Salumets, Andres and Khaw, Kay Tee and Langenberg, Claudia and Wareham, Nicholas J and Isaacs, Aaron and Kraja, Aldi and Zhang, Qunyuan and Wild, Philipp S and Scott, Rodney J and Holliday, Elizabeth G and Org, Elin and Viigimaa, Margus and Bandinelli, Stefania and Metter, Jeffrey E and Lupo, Antonio and Trabetti, Elisabetta and Sorice, Rossella and D{\"o}ring, Angela and Lattka, Eva and Strauch, Konstantin and Theis, Fabian and Waldenberger, Melanie and Wichmann, H-Erich and Davies, Gail and Gow, Alan J and Bruinenberg, Marcel and Stolk, Ronald P and Kooner, Jaspal S and Zhang, Weihua and Winkelmann, Bernhard R and Boehm, Bernhard O and Lucae, Susanne and Penninx, Brenda W and Smit, Johannes H and Curhan, Gary and Mudgal, Poorva and Plenge, Robert M and Portas, Laura and Persico, Ivana and Kirin, Mirna and Wilson, James F and Mateo Leach, Irene and van Gilst, Wiek H and Goel, Anuj and Ongen, Halit and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Imboden, Medea and von Eckardstein, Arnold and Cucca, Francesco and Nagaraja, Ramaiah and Piras, Maria Grazia and Nauck, Matthias and Schurmann, Claudia and Budde, Kathrin and Ernst, Florian and Farrington, Susan M and Theodoratou, Evropi and Prokopenko, Inga and Stumvoll, Michael and Jula, Antti and Perola, Markus and Salomaa, Veikko and Shin, So-Youn and Spector, Tim D and Sala, Cinzia and Ridker, Paul M and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Hengstenberg, Christian and Nelson, Christopher P and Meschia, James F and Nalls, Michael A and Sharma, Pankaj and Singleton, Andrew B and Kamatani, Naoyuki and Zeller, Tanja and Burnier, Michel and Attia, John and Laan, Maris and Klopp, Norman and Hillege, Hans L and Kloiber, Stefan and Choi, Hyon and Pirastu, Mario and Tore, Silvia and Probst-Hensch, Nicole M and V{\"o}lzke, Henry and Gudnason, Vilmundur and Parsa, Afshin and Schmidt, Reinhold and Whitfield, John B and Fornage, Myriam and Gasparini, Paolo and Siscovick, David S and Polasek, Ozren and Campbell, Harry and Rudan, Igor and Bouatia-Naji, Nabila and Metspalu, Andres and Loos, Ruth J F and van Duijn, Cornelia M and Borecki, Ingrid B and Ferrucci, Luigi and Gambaro, Giovanni and Deary, Ian J and Wolffenbuttel, Bruce H R and Chambers, John C and M{\"a}rz, Winfried and Pramstaller, Peter P and Snieder, Harold and Gyllensten, Ulf and Wright, Alan F and Navis, Gerjan and Watkins, Hugh and Witteman, Jacqueline C M and Sanna, Serena and Schipf, Sabine and Dunlop, Malcolm G and T{\"o}njes, Anke and Ripatti, Samuli and Soranzo, Nicole and Toniolo, Daniela and Chasman, Daniel I and Raitakari, Olli and Kao, W H Linda and Ciullo, Marina and Fox, Caroline S and Caulfield, Mark and Bochud, Murielle and Gieger, Christian} } @article {1958, title = {Evidence of inbreeding depression on human height.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002655}, abstract = {

Stature is a classical and highly heritable complex trait, with 80\%-90\% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ(2) = 83.89, df = 1; p = 5.2 {\texttimes} 10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

}, keywords = {Adult, Aged, Body Height, Consanguinity, Databases, Genetic, Family, Female, Genes, Recessive, Genetic Heterogeneity, Genome-Wide Association Study, Homozygote, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002655}, author = {McQuillan, Ruth and Eklund, Niina and Pirastu, Nicola and Kuningas, Maris and McEvoy, Brian P and Esko, T{\~o}nu and Corre, Tanguy and Davies, Gail and Kaakinen, Marika and Lyytik{\"a}inen, Leo-Pekka and Kristiansson, Kati and Havulinna, Aki S and G{\"o}gele, Martin and Vitart, Veronique and Tenesa, Albert and Aulchenko, Yurii and Hayward, Caroline and Johansson, {\r A}sa and Boban, Mladen and Ulivi, Sheila and Robino, Antonietta and Boraska, Vesna and Igl, Wilmar and Wild, Sarah H and Zgaga, Lina and Amin, Najaf and Theodoratou, Evropi and Polasek, Ozren and Girotto, Giorgia and Lopez, Lorna M and Sala, Cinzia and Lahti, Jari and Laatikainen, Tiina and Prokopenko, Inga and Kals, Mart and Viikari, Jorma and Yang, Jian and Pouta, Anneli and Estrada, Karol and Hofman, Albert and Freimer, Nelson and Martin, Nicholas G and K{\"a}h{\"o}nen, Mika and Milani, Lili and Heli{\"o}vaara, Markku and Vartiainen, Erkki and R{\"a}ikk{\"o}nen, Katri and Masciullo, Corrado and Starr, John M and Hicks, Andrew A and Esposito, Laura and Kolcic, Ivana and Farrington, Susan M and Oostra, Ben and Zemunik, Tatijana and Campbell, Harry and Kirin, Mirna and Pehlic, Marina and Faletra, Flavio and Porteous, David and Pistis, Giorgio and Widen, Elisabeth and Salomaa, Veikko and Koskinen, Seppo and Fischer, Krista and Lehtim{\"a}ki, Terho and Heath, Andrew and McCarthy, Mark I and Rivadeneira, Fernando and Montgomery, Grant W and Tiemeier, Henning and Hartikainen, Anna-Liisa and Madden, Pamela A F and d{\textquoteright}Adamo, Pio and Hastie, Nicholas D and Gyllensten, Ulf and Wright, Alan F and van Duijn, Cornelia M and Dunlop, Malcolm and Rudan, Igor and Gasparini, Paolo and Pramstaller, Peter P and Deary, Ian J and Toniolo, Daniela and Eriksson, Johan G and Jula, Antti and Raitakari, Olli T and Metspalu, Andres and Perola, Markus and J{\"a}rvelin, Marjo-Riitta and Uitterlinden, Andr{\'e} and Visscher, Peter M and Wilson, James F} } @article {1907, title = {Genome-wide association and functional follow-up reveals new loci for kidney function.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002584}, abstract = {

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

}, keywords = {African Americans, Aged, Animals, Caspase 9, Cyclin-Dependent Kinases, DEAD-box RNA Helicases, DNA Helicases, European Continental Ancestry Group, Female, Follow-Up Studies, Gene Knockdown Techniques, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Male, Middle Aged, Phosphoric Diester Hydrolases, Zebrafish}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002584}, author = {Pattaro, Cristian and K{\"o}ttgen, Anna and Teumer, Alexander and Garnaas, Maija and B{\"o}ger, Carsten A and Fuchsberger, Christian and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Taliun, Daniel and Li, Man and Gao, Xiaoyi and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C and O{\textquoteright}Seaghdha, Conall M and Glazer, Nicole and Isaacs, Aaron and Liu, Ching-Ti and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Johnson, Andrew D and Gierman, Hinco J and Feitosa, Mary and Hwang, Shih-Jen and Atkinson, Elizabeth J and Lohman, Kurt and Cornelis, Marilyn C and Johansson, {\r A}sa and T{\"o}njes, Anke and Dehghan, Abbas and Chouraki, Vincent and Holliday, Elizabeth G and Sorice, Rossella and Kutalik, Zolt{\'a}n and Lehtim{\"a}ki, Terho and Esko, T{\~o}nu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y and Murgia, Federico and Trompet, Stella and Imboden, Medea and Kollerits, Barbara and Pistis, Giorgio and Harris, Tamara B and Launer, Lenore J and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D and Boerwinkle, Eric and Schmidt, Helena and Cavalieri, Margherita and Rao, Madhumathi and Hu, Frank B and Demirkan, Ayse and Oostra, Ben A and de Andrade, Mariza and Turner, Stephen T and Ding, Jingzhong and Andrews, Jeanette S and Freedman, Barry I and Koenig, Wolfgang and Illig, Thomas and D{\"o}ring, Angela and Wichmann, H-Erich and Kolcic, Ivana and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and N{\"o}thlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Endlich, Karlhans and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K and Nauck, Matthias and Stracke, Sylvia and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Kovacs, Peter and Stumvoll, Michael and M{\"a}gi, Reedik and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Aulchenko, Yurii S and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Ruggiero, Daniela and Bergmann, Sven and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Ketkar, Shamika and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Giulianini, Franco and Kr{\"a}mer, Bernhard K and Portas, Laura and Ford, Ian and Buckley, Brendan M and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Metzger, Marie and Mitchell, Paul and Ciullo, Marina and Kim, Stuart K and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J Wouter and Probst-Hensch, Nicole M and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Siscovick, David S and van Duijn, Cornelia M and Borecki, Ingrid and Kardia, Sharon L R and Liu, Yongmei and Curhan, Gary C and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Franke, Andre and Pramstaller, Peter P and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline C M and Hayward, Caroline and Ridker, Paul and Parsa, Afshin and Bochud, Murielle and Heid, Iris M and Goessling, Wolfram and Chasman, Daniel I and Kao, W H Linda and Fox, Caroline S} } @article {1980, title = {Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function.}, journal = {Hum Mol Genet}, volume = {21}, year = {2012}, month = {2012 Dec 15}, pages = {5329-43}, abstract = {

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 {\texttimes} 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 {\texttimes} 10(-4)-2.2 {\texttimes} 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

}, keywords = {Amino Acid Transport Systems, Basic, Antigens, CD98 Heavy Chain, Genetic Predisposition to Disease, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Inhibin-beta Subunits, Intracellular Signaling Peptides and Proteins, Low Density Lipoprotein Receptor-Related Protein-2, Membrane Proteins, Polymorphism, Single Nucleotide}, issn = {1460-2083}, doi = {10.1093/hmg/dds369}, author = {Chasman, Daniel I and Fuchsberger, Christian and Pattaro, Cristian and Teumer, Alexander and B{\"o}ger, Carsten A and Endlich, Karlhans and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Taliun, Daniel and Li, Man and Gao, Xiaoyi and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C and O{\textquoteright}Seaghdha, Conall M and Glazer, Nicole and Isaacs, Aaron and Liu, Ching-Ti and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Johnson, Andrew D and Gierman, Hinco J and Feitosa, Mary F and Hwang, Shih-Jen and Atkinson, Elizabeth J and Lohman, Kurt and Cornelis, Marilyn C and Johansson, {\r A}sa and T{\"o}njes, Anke and Dehghan, Abbas and Lambert, Jean-Charles and Holliday, Elizabeth G and Sorice, Rossella and Kutalik, Zolt{\'a}n and Lehtim{\"a}ki, Terho and Esko, T{\~o}nu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y and Murgia, Federico and Trompet, Stella and Imboden, Medea and Coassin, Stefan and Pistis, Giorgio and Harris, Tamara B and Launer, Lenore J and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D and Boerwinkle, Eric and Schmidt, Helena and Cavalieri, Margherita and Rao, Madhumathi and Hu, Frank and Demirkan, Ayse and Oostra, Ben A and de Andrade, Mariza and Turner, Stephen T and Ding, Jingzhong and Andrews, Jeanette S and Freedman, Barry I and Giulianini, Franco and Koenig, Wolfgang and Illig, Thomas and Meisinger, Christa and Gieger, Christian and Zgaga, Lina and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and N{\"o}thlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K and Nauck, Matthias and Stracke, Sylvia and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Kovacs, Peter and Stumvoll, Michael and M{\"a}gi, Reedik and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Aulchenko, Yurii S and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Stengel, B{\'e}n{\'e}dicte and Ruggiero, Daniela and Bergmann, Sven and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Ketkar, Shamika and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Kr{\"a}mer, Bernhard K and Portas, Laura and Ford, Ian and Buckley, Brendan M and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Mitchell, Paul and Ciullo, Marina and Kim, Stuart K and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J Wouter and Probst-Hensch, Nicole M and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Siscovick, David S and van Duijn, Cornelia M and Borecki, Ingrid B and Kardia, Sharon L R and Liu, Yongmei and Curhan, Gary C and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Franke, Andre and Pramstaller, Peter P and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline and Hayward, Caroline and Ridker, Paul M and Parsa, Afshin and Bochud, Murielle and Heid, Iris M and Kao, W H Linda and Fox, Caroline S and K{\"o}ttgen, Anna} } @article {1906, title = {Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Mar}, pages = {260-8}, abstract = {

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 {\texttimes} 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

}, keywords = {Age Factors, DNA Helicases, DNA Primase, DNA Repair, DNA Repair Enzymes, DNA-Directed DNA Polymerase, European Continental Ancestry Group, Exodeoxyribonucleases, Female, Genetic Loci, Genome-Wide Association Study, Humans, Immunity, Menopause, Polymorphism, Single Nucleotide, Proteins}, issn = {1546-1718}, doi = {10.1038/ng.1051}, author = {Stolk, Lisette and Perry, John R B and Chasman, Daniel I and He, Chunyan and Mangino, Massimo and Sulem, Patrick and Barbalic, Maja and Broer, Linda and Byrne, Enda M and Ernst, Florian and Esko, T{\~o}nu and Franceschini, Nora and Gudbjartsson, Daniel F and Hottenga, Jouke-Jan and Kraft, Peter and McArdle, Patrick F and Porcu, Eleonora and Shin, So-Youn and Smith, Albert V and van Wingerden, Sophie and Zhai, Guangju and Zhuang, Wei V and Albrecht, Eva and Alizadeh, Behrooz Z and Aspelund, Thor and Bandinelli, Stefania and Lauc, Lovorka Barac and Beckmann, Jacques S and Boban, Mladen and Boerwinkle, Eric and Broekmans, Frank J and Burri, Andrea and Campbell, Harry and Chanock, Stephen J and Chen, Constance and Cornelis, Marilyn C and Corre, Tanguy and Coviello, Andrea D and d{\textquoteright}Adamo, Pio and Davies, Gail and de Faire, Ulf and de Geus, Eco J C and Deary, Ian J and Dedoussis, George V Z and Deloukas, Panagiotis and Ebrahim, Shah and Eiriksdottir, Gudny and Emilsson, Valur and Eriksson, Johan G and Fauser, Bart C J M and Ferreli, Liana and Ferrucci, Luigi and Fischer, Krista and Folsom, Aaron R and Garcia, Melissa E and Gasparini, Paolo and Gieger, Christian and Glazer, Nicole and Grobbee, Diederick E and Hall, Per and Haller, Toomas and Hankinson, Susan E and Hass, Merli and Hayward, Caroline and Heath, Andrew C and Hofman, Albert and Ingelsson, Erik and Janssens, A Cecile J W and Johnson, Andrew D and Karasik, David and Kardia, Sharon L R and Keyzer, Jules and Kiel, Douglas P and Kolcic, Ivana and Kutalik, Zolt{\'a}n and Lahti, Jari and Lai, Sandra and Laisk, Triin and Laven, Joop S E and Lawlor, Debbie A and Liu, Jianjun and Lopez, Lorna M and Louwers, Yvonne V and Magnusson, Patrik K E and Marongiu, Mara and Martin, Nicholas G and Klaric, Irena Martinovic and Masciullo, Corrado and McKnight, Barbara and Medland, Sarah E and Melzer, David and Mooser, Vincent and Navarro, Pau and Newman, Anne B and Nyholt, Dale R and Onland-Moret, N Charlotte and Palotie, Aarno and Par{\'e}, Guillaume and Parker, Alex N and Pedersen, Nancy L and Peeters, Petra H M and Pistis, Giorgio and Plump, Andrew S and Polasek, Ozren and Pop, Victor J M and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Rehnberg, Emil and Rotter, Jerome I and Rudan, Igor and Sala, Cinzia and Salumets, Andres and Scuteri, Angelo and Singleton, Andrew and Smith, Jennifer A and Snieder, Harold and Soranzo, Nicole and Stacey, Simon N and Starr, John M and Stathopoulou, Maria G and Stirrups, Kathleen and Stolk, Ronald P and Styrkarsdottir, Unnur and Sun, Yan V and Tenesa, Albert and Thorand, Barbara and Toniolo, Daniela and Tryggvadottir, Laufey and Tsui, Kim and Ulivi, Sheila and van Dam, Rob M and van der Schouw, Yvonne T and van Gils, Carla H and van Nierop, Peter and Vink, Jacqueline M and Visscher, Peter M and Voorhuis, Marlies and Waeber, Gerard and Wallaschofski, Henri and Wichmann, H Erich and Widen, Elisabeth and Wijnands-van Gent, Colette J M and Willemsen, Gonneke and Wilson, James F and Wolffenbuttel, Bruce H R and Wright, Alan F and Yerges-Armstrong, Laura M and Zemunik, Tatijana and Zgaga, Lina and Zillikens, M Carola and Zygmunt, Marek and Arnold, Alice M and Boomsma, Dorret I and Buring, Julie E and Crisponi, Laura and Demerath, Ellen W and Gudnason, Vilmundur and Harris, Tamara B and Hu, Frank B and Hunter, David J and Launer, Lenore J and Metspalu, Andres and Montgomery, Grant W and Oostra, Ben A and Ridker, Paul M and Sanna, Serena and Schlessinger, David and Spector, Tim D and Stefansson, Kari and Streeten, Elizabeth A and Thorsteinsdottir, Unnur and Uda, Manuela and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and V{\"o}lzke, Henry and Murray, Anna and Murabito, Joanne M and Visser, Jenny A and Lunetta, Kathryn L} } @article {1703, title = {Association of a variant in the CHRNA5-A3-B4 gene cluster region to heavy smoking in the Italian population.}, journal = {Eur J Hum Genet}, volume = {19}, year = {2011}, month = {2011 May}, pages = {593-6}, abstract = {

Large-scale population studies have established that genetic factors contribute to individual differences in smoking behavior. Linkage and genome-wide association studies have shown many chromosomal regions and genes associated with different smoking behaviors. One study was the association of single-nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 gene cluster to nicotine addiction. Here, we report a replication of this association in the Italian population represented by three genetically isolated populations. One, the Val Borbera, is a genetic isolate from North-Western Italy; the Cilento population, is located in South-Western Italy; and the Carlantino village is located in South-Eastern Italy. Owing to their position and their isolation, the three populations have a different environment, different history and genetic structure. The variant A of the rs1051730 SNP was significantly associated with smoking quantity in two populations, Val Borbera and Cilento, no association was found in Carlantino population probably because difference in LD pattern in the variant region.

}, keywords = {Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Italy, Multigene Family, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Receptors, Nicotinic, Smoking, Tobacco Use Disorder}, issn = {1476-5438}, doi = {10.1038/ejhg.2010.240}, author = {Sorice, Rossella and Bione, Silvia and Sansanelli, Serena and Ulivi, Sheila and Athanasakis, Emmanouil and Lanzara, Carmela and Nutile, Teresa and Sala, Cinzia and Camaschella, Clara and d{\textquoteright}Adamo, Pio and Gasparini, Paolo and Ciullo, Marina and Toniolo, Daniela} } @article {1840, title = {Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Oct}, pages = {1005-11}, abstract = {

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 {\texttimes} 10(-8) to P = 2.3 {\texttimes} 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

}, keywords = {Arteries, Blood Pressure, Case-Control Studies, Follow-Up Studies, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Linkage Disequilibrium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.922}, author = {Wain, Louise V and Verwoert, Germaine C and O{\textquoteright}Reilly, Paul F and Shi, Gang and Johnson, Toby and Johnson, Andrew D and Bochud, Murielle and Rice, Kenneth M and Henneman, Peter and Smith, Albert V and Ehret, Georg B and Amin, Najaf and Larson, Martin G and Mooser, Vincent and Hadley, David and D{\"o}rr, Marcus and Bis, Joshua C and Aspelund, Thor and Esko, T{\~o}nu and Janssens, A Cecile J W and Zhao, Jing Hua and Heath, Simon and Laan, Maris and Fu, Jingyuan and Pistis, Giorgio and Luan, Jian{\textquoteright}an and Arora, Pankaj and Lucas, Gavin and Pirastu, Nicola and Pichler, Irene and Jackson, Anne U and Webster, Rebecca J and Zhang, Feng and Peden, John F and Schmidt, Helena and Tanaka, Toshiko and Campbell, Harry and Igl, Wilmar and Milaneschi, Yuri and Hottenga, Jouke-Jan and Vitart, Veronique and Chasman, Daniel I and Trompet, Stella and Bragg-Gresham, Jennifer L and Alizadeh, Behrooz Z and Chambers, John C and Guo, Xiuqing and Lehtim{\"a}ki, Terho and Kuhnel, Brigitte and Lopez, Lorna M and Polasek, Ozren and Boban, Mladen and Nelson, Christopher P and Morrison, Alanna C and Pihur, Vasyl and Ganesh, Santhi K and Hofman, Albert and Kundu, Suman and Mattace-Raso, Francesco U S and Rivadeneira, Fernando and Sijbrands, Eric J G and Uitterlinden, Andr{\'e} G and Hwang, Shih-Jen and Vasan, Ramachandran S and Wang, Thomas J and Bergmann, Sven and Vollenweider, Peter and Waeber, Gerard and Laitinen, Jaana and Pouta, Anneli and Zitting, Paavo and McArdle, Wendy L and Kroemer, Heyo K and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Glazer, Nicole L and Taylor, Kent D and Harris, Tamara B and Alavere, Helene and Haller, Toomas and Keis, Aime and Tammesoo, Mari-Liis and Aulchenko, Yurii and Barroso, In{\^e}s and Khaw, Kay-Tee and Galan, Pilar and Hercberg, Serge and Lathrop, Mark and Eyheramendy, Susana and Org, Elin and S{\~o}ber, Siim and Lu, Xiaowen and Nolte, Ilja M and Penninx, Brenda W and Corre, Tanguy and Masciullo, Corrado and Sala, Cinzia and Groop, Leif and Voight, Benjamin F and Melander, Olle and O{\textquoteright}Donnell, Christopher J and Salomaa, Veikko and d{\textquoteright}Adamo, Adamo Pio and Fabretto, Antonella and Faletra, Flavio and Ulivi, Sheila and Del Greco, Fabiola M and Facheris, Maurizio and Collins, Francis S and Bergman, Richard N and Beilby, John P and Hung, Joseph and Musk, A William and Mangino, Massimo and Shin, So-Youn and Soranzo, Nicole and Watkins, Hugh and Goel, Anuj and Hamsten, Anders and Gider, Pierre and Loitfelder, Marisa and Zeginigg, Marion and Hernandez, Dena and Najjar, Samer S and Navarro, Pau and Wild, Sarah H and Corsi, Anna Maria and Singleton, Andrew and de Geus, Eco J C and Willemsen, Gonneke and Parker, Alex N and Rose, Lynda M and Buckley, Brendan and Stott, David and Orru, Marco and Uda, Manuela and van der Klauw, Melanie M and Zhang, Weihua and Li, Xinzhong and Scott, James and Chen, Yii-Der Ida and Burke, Gregory L and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and D{\"o}ring, Angela and Meitinger, Thomas and Davies, Gail and Starr, John M and Emilsson, Valur and Plump, Andrew and Lindeman, Jan H and Hoen, Peter A C {\textquoteright}t and K{\"o}nig, Inke R and Felix, Janine F and Clarke, Robert and Hopewell, Jemma C and Ongen, Halit and Breteler, Monique and Debette, St{\'e}phanie and Destefano, Anita L and Fornage, Myriam and Mitchell, Gary F and Smith, Nicholas L and Holm, Hilma and Stefansson, Kari and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Samani, Nilesh J and Preuss, Michael and Rudan, Igor and Hayward, Caroline and Deary, Ian J and Wichmann, H-Erich and Raitakari, Olli T and Palmas, Walter and Kooner, Jaspal S and Stolk, Ronald P and Jukema, J Wouter and Wright, Alan F and Boomsma, Dorret I and Bandinelli, Stefania and Gyllensten, Ulf B and Wilson, James F and Ferrucci, Luigi and Schmidt, Reinhold and Farrall, Martin and Spector, Tim D and Palmer, Lyle J and Tuomilehto, Jaakko and Pfeufer, Arne and Gasparini, Paolo and Siscovick, David and Altshuler, David and Loos, Ruth J F and Toniolo, Daniela and Snieder, Harold and Gieger, Christian and Meneton, Pierre and Wareham, Nicholas J and Oostra, Ben A and Metspalu, Andres and Launer, Lenore and Rettig, Rainer and Strachan, David P and Beckmann, Jacques S and Witteman, Jacqueline C M and Erdmann, Jeanette and van Dijk, Ko Willems and Boerwinkle, Eric and Boehnke, Michael and Ridker, Paul M and J{\"a}rvelin, Marjo-Riitta and Chakravarti, Aravinda and Abecasis, Goncalo R and Gudnason, Vilmundur and Newton-Cheh, Christopher and Levy, Daniel and Munroe, Patricia B and Psaty, Bruce M and Caulfield, Mark J and Rao, Dabeeru C and Tobin, Martin D and Elliott, Paul and van Duijn, Cornelia M} } @article {1723, title = {Hearing function and thresholds: a genome-wide association study in European isolated populations identifies new loci and pathways.}, journal = {J Med Genet}, volume = {48}, year = {2011}, month = {2011 Jun}, pages = {369-74}, abstract = {

BACKGROUND: Hearing is a complex trait, but until now only a few genes are known to contribute to variability of this process. In order to discover genes and pathways that underlie auditory function, a genome-wide association study was carried out within the International Consortium G-EAR.

METHODS: Meta-analysis of genome-wide association study{\textquoteright}s data from six isolated populations of European ancestry for an overall number of 3417 individuals.

RESULTS: Eight suggestive significant loci (p<10(-7)) were detected with a series of genes expressed within the inner ear such as: DCLK1, PTPRD, GRM8, CMIP. Additional biological candidates marked by a single nucleotide polymorphism (SNP) with a suggestive association (p<10(-6)) were identified, as well as loci encompassing {\textquoteright}gene desert regions{\textquoteright}-genes of unknown function or genes whose function has not be linked to hearing so far. Some of these new loci map to already known hereditary hearing loss loci whose genes still need to be identified. Data have also been used to construct a highly significant {\textquoteright}in silico{\textquoteright} pathway for hearing function characterised by a network of 49 genes, 34 of which are certainly expressed in the ear.

CONCLUSION: These results provide new insights into the molecular basis of hearing function and may suggest new targets for hearing impairment treatment and prevention.

}, keywords = {Adaptor Proteins, Signal Transducing, Animals, Auditory Threshold, Carrier Proteins, Databases, Genetic, Europe, European Continental Ancestry Group, Female, Founder Effect, Genetic Linkage, Genome-Wide Association Study, Hearing, Hearing Loss, Humans, Intracellular Signaling Peptides and Proteins, Male, Mice, Phenotype, Polymorphism, Single Nucleotide, Protein-Serine-Threonine Kinases, Receptor-Like Protein Tyrosine Phosphatases, Class 2, Receptors, Metabotropic Glutamate}, issn = {1468-6244}, doi = {10.1136/jmg.2010.088310}, author = {Girotto, Giorgia and Pirastu, Nicola and Sorice, Rossella and Biino, Ginevra and Campbell, Harry and d{\textquoteright}Adamo, Adamo P and Hastie, Nicholas D and Nutile, Teresa and Polasek, Ozren and Portas, Laura and Rudan, Igor and Ulivi, Sheila and Zemunik, Tatijana and Wright, Alan F and Ciullo, Marina and Hayward, Caroline and Pirastu, Mario and Gasparini, Paolo} } @article {1693, title = {Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1.}, journal = {J Nephrol}, volume = {23}, year = {2010}, month = {2010 Nov-Dec}, pages = {667-76}, abstract = {

INTRODUCTION: Mutations of the AGXT gene encoding the alanine:glyoxylate aminotransferase liver enzyme (AGT) cause primary hyperoxaluria type 1 (PH1). Here we report a molecular modeling study of selected missense AGXT mutations: the common Gly170Arg and the recently described Gly47Arg and Ser81Leu variants, predicted to be pathogenic using standard criteria.

METHODS: Taking advantage of the refined 3D structure of AGT, we computed the dimerization energy of the wild-type and mutated proteins.

RESULTS: Molecular modeling predicted that Gly47Arg affects dimerization with a similar effect to that shown previously for Gly170Arg through classical biochemical approaches. In contrast, no effect on dimerization was predicted for Ser81Leu. Therefore, this probably demonstrates pathogenic properties via a different mechanism, similar to that described for the adjacent Gly82Glu mutation that affects pyridoxine binding.

CONCLUSION: This study shows that the molecular modeling approach can contribute to evaluating the pathogenicity of some missense variants that affect dimerization. However, in silico studies--aimed to assess the relationship between structural change and biological effects--require the integrated use of more than 1 tool.

}, keywords = {Amino Acid Sequence, Female, Humans, Male, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Protein Multimerization, Transaminases}, issn = {1121-8428}, author = {Robbiano, Angela and Frecer, Vladimir and Miertus, Jan and Zadro, Cristina and Ulivi, Sheila and Bevilacqua, Elena and Mandrile, Giorgia and De Marchi, Mario and Miertus, Stanislav and Amoroso, Antonio} }