@article {10444, title = {Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Jun}, pages = {834-848}, abstract = {

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0127-7}, author = {Tedja, Milly S and Wojciechowski, Robert and Hysi, Pirro G and Eriksson, Nicholas and Furlotte, Nicholas A and Verhoeven, Virginie J M and Iglesias, Adriana I and Meester-Smoor, Magda A and Tompson, Stuart W and Fan, Qiao and Khawaja, Anthony P and Cheng, Ching-Yu and H{\"o}hn, Ren{\'e} and Yamashiro, Kenji and Wenocur, Adam and Grazal, Clare and Haller, Toomas and Metspalu, Andres and Wedenoja, Juho and Jonas, Jost B and Wang, Ya Xing and Xie, Jing and Mitchell, Paul and Foster, Paul J and Klein, Barbara E K and Klein, Ronald and Paterson, Andrew D and Hosseini, S Mohsen and Shah, Rupal L and Williams, Cathy and Teo, Yik Ying and Tham, Yih Chung and Gupta, Preeti and Zhao, Wanting and Shi, Yuan and Saw, Woei-Yuh and Tai, E-Shyong and Sim, Xue Ling and Huffman, Jennifer E and Polasek, Ozren and Hayward, Caroline and Bencic, Goran and Rudan, Igor and Wilson, James F and Joshi, Peter K and Tsujikawa, Akitaka and Matsuda, Fumihiko and Whisenhunt, Kristina N and Zeller, Tanja and van der Spek, Peter J and Haak, Roxanna and Meijers-Heijboer, Hanne and van Leeuwen, Elisabeth M and Iyengar, Sudha K and Lass, Jonathan H and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Vingerling, Johannes R and Lehtim{\"a}ki, Terho and Raitakari, Olli T and Biino, Ginevra and Concas, Maria Pina and Schwantes-An, Tae-Hwi and Igo, Robert P and Cuellar-Partida, Gabriel and Martin, Nicholas G and Craig, Jamie E and Gharahkhani, Puya and Williams, Katie M and Nag, Abhishek and Rahi, Jugnoo S and Cumberland, Phillippa M and Delcourt, C{\'e}cile and Bellenguez, C{\'e}line and Ried, Janina S and Bergen, Arthur A and Meitinger, Thomas and Gieger, Christian and Wong, Tien Yin and Hewitt, Alex W and Mackey, David A and Simpson, Claire L and Pfeiffer, Norbert and P{\"a}rssinen, Olavi and Baird, Paul N and Vitart, Veronique and Amin, Najaf and van Duijn, Cornelia M and Bailey-Wilson, Joan E and Young, Terri L and Saw, Seang-Mei and Stambolian, Dwight and MacGregor, Stuart and Guggenheim, Jeremy A and Tung, Joyce Y and Hammond, Christopher J and Klaver, Caroline C W} } @article {10426, title = {A genome-wide association study of corneal astigmatism: The CREAM Consortium.}, journal = {Mol Vis}, volume = {24}, year = {2018}, month = {2018}, pages = {127-142}, abstract = {

Purpose: To identify genes and genetic markers associated with corneal astigmatism.

Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression.

Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha () gene: top SNP: rs7673984, odds ratio=1.12 (95\% CI:1.08-1.16), p=5.55{\texttimes}10. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (), acid phosphatase 2, lysosomal (), and TNF alpha-induced protein 8 like 3 ().

Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the gene, gene-based analysis identified three novel candidate genes, , , and , that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

}, keywords = {Acid Phosphatase, Asian Continental Ancestry Group, Astigmatism, Claudins, Cohort Studies, Cornea, Corneal Diseases, European Continental Ancestry Group, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Odds Ratio, Polymorphism, Single Nucleotide, Receptor, Platelet-Derived Growth Factor alpha, Software}, issn = {1090-0535}, author = {Shah, Rupal L and Li, Qing and Zhao, Wanting and Tedja, Milly S and Tideman, J Willem L and Khawaja, Anthony P and Fan, Qiao and Yazar, Seyhan and Williams, Katie M and Verhoeven, Virginie J M and Xie, Jing and Wang, Ya Xing and Hess, Moritz and Nickels, Stefan and Lackner, Karl J and P{\"a}rssinen, Olavi and Wedenoja, Juho and Biino, Ginevra and Concas, Maria Pina and Uitterlinden, Andr{\'e} and Rivadeneira, Fernando and Jaddoe, Vincent W V and Hysi, Pirro G and Sim, Xueling and Tan, Nicholas and Tham, Yih-Chung and Sensaki, Sonoko and Hofman, Albert and Vingerling, Johannes R and Jonas, Jost B and Mitchell, Paul and Hammond, Christopher J and H{\"o}hn, Ren{\'e} and Baird, Paul N and Wong, Tien-Yin and Cheng, Chinfsg-Yu and Teo, Yik Ying and Mackey, David A and Williams, Cathy and Saw, Seang-Mei and Klaver, Caroline C W and Guggenheim, Jeremy A and Bailey-Wilson, Joan E} } @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 {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 {10557, title = {Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jun 01}, pages = {865-884}, abstract = {

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71\% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

}, keywords = {Anthropometry, Body Height, Cohort Studies, Databases, Genetic, DNA Methylation, Female, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Lipodystrophy, Male, Meta-Analysis as Topic, Obesity, Physical Chromosome Mapping, Quantitative Trait Loci, Sequence Analysis, DNA, Sex Characteristics, Syndrome, United Kingdom}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.04.014}, author = {Tachmazidou, Ioanna and S{\"u}veges, D{\'a}niel and Min, Josine L and Ritchie, Graham R S and Steinberg, Julia and Walter, Klaudia and Iotchkova, Valentina and Schwartzentruber, Jeremy and Huang, Jie and Memari, Yasin and McCarthy, Shane and Crawford, Andrew A and Bombieri, Cristina and Cocca, Massimiliano and Farmaki, Aliki-Eleni and Gaunt, Tom R and Jousilahti, Pekka and Kooijman, Marjolein N and Lehne, Benjamin and Malerba, Giovanni and M{\"a}nnist{\"o}, Satu and Matchan, Angela and Medina-Gomez, Carolina and Metrustry, Sarah J and Nag, Abhishek and Ntalla, Ioanna and Paternoster, Lavinia and Rayner, Nigel W and Sala, Cinzia and Scott, William R and Shihab, Hashem A and Southam, Lorraine and St Pourcain, Beate and Traglia, Michela and Trajanoska, Katerina and Zaza, Gialuigi and Zhang, Weihua and Artigas, Mar{\'\i}a S and Bansal, Narinder and Benn, Marianne and Chen, Zhongsheng and Danecek, Petr and Lin, Wei-Yu and Locke, Adam and Luan, Jian{\textquoteright}an and Manning, Alisa K and Mulas, Antonella and Sidore, Carlo and Tybjaerg-Hansen, Anne and Varbo, Anette and Zoledziewska, Magdalena and Finan, Chris and Hatzikotoulas, Konstantinos and Hendricks, Audrey E and Kemp, John P and Moayyeri, Alireza and Panoutsopoulou, Kalliope and Szpak, Michal and Wilson, Scott G and Boehnke, Michael and Cucca, Francesco and Di Angelantonio, Emanuele and Langenberg, Claudia and Lindgren, Cecilia and McCarthy, Mark I and Morris, Andrew P and Nordestgaard, B{\o}rge G and Scott, Robert A and Tobin, Martin D and Wareham, Nicholas J and Burton, Paul and Chambers, John C and Smith, George Davey and Dedoussis, George and Felix, Janine F and Franco, Oscar H and Gambaro, Giovanni and Gasparini, Paolo and Hammond, Christopher J and Hofman, Albert and Jaddoe, Vincent W V and Kleber, Marcus and Kooner, Jaspal S and Perola, Markus and Relton, Caroline and Ring, Susan M and Rivadeneira, Fernando and Salomaa, Veikko and Spector, Timothy D and Stegle, Oliver and Toniolo, Daniela and Uitterlinden, Andr{\'e} G and Barroso, In{\^e}s and Greenwood, Celia M T and Perry, John R B and Walker, Brian R and Butterworth, Adam S and Xue, Yali and Durbin, Richard and Small, Kerrin S and Soranzo, Nicole and Timpson, Nicholas J and Zeggini, Eleftheria} } @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 {7691, title = {Genetic studies of body mass index yield new insights for obesity biology.}, journal = {Nature}, volume = {518}, year = {2015}, month = {2015 Feb 12}, pages = {197-206}, abstract = {

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P~<~5~{\texttimes}~10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for \~{}2.7\% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20\% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

}, keywords = {Adipogenesis, Adiposity, Age Factors, Body Mass Index, Continental Population Groups, Energy Metabolism, Europe, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Glutamic Acid, Humans, Insulin, Male, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Synapses}, issn = {1476-4687}, doi = {10.1038/nature14177}, author = {Locke, Adam E and Kahali, Bratati and Berndt, Sonja I and Justice, Anne E and Pers, Tune H and Day, Felix R and Powell, Corey and Vedantam, Sailaja and Buchkovich, Martin L and Yang, Jian and Croteau-Chonka, Damien C and Esko, T{\~o}nu and Fall, Tove and Ferreira, Teresa and Gustafsson, Stefan and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Randall, Joshua C and Winkler, Thomas W and Wood, Andrew R and Workalemahu, Tsegaselassie and Faul, Jessica D and Smith, Jennifer A and Hua Zhao, Jing and Zhao, Wei and Chen, Jin and Fehrmann, Rudolf and Hedman, {\r A}sa K and Karjalainen, Juha and Schmidt, Ellen M and Absher, Devin and Amin, Najaf and Anderson, Denise and Beekman, Marian and Bolton, Jennifer L and Bragg-Gresham, Jennifer L and Buyske, Steven and Demirkan, Ayse and Deng, Guohong and Ehret, Georg B and Feenstra, Bjarke and Feitosa, Mary F and Fischer, Krista and Goel, Anuj and Gong, Jian and Jackson, Anne U and Kanoni, Stavroula and Kleber, Marcus E and Kristiansson, Kati and Lim, Unhee and Lotay, Vaneet and Mangino, Massimo and Mateo Leach, Irene and Medina-Gomez, Carolina and Medland, Sarah E and Nalls, Michael A and Palmer, Cameron D and Pasko, Dorota and Pechlivanis, Sonali and Peters, Marjolein J and Prokopenko, Inga and Shungin, Dmitry and Stan{\v c}{\'a}kov{\'a}, Alena and Strawbridge, Rona J and Ju Sung, Yun and Tanaka, Toshiko and Teumer, Alexander and Trompet, Stella and van der Laan, Sander W and van Setten, Jessica and Van Vliet-Ostaptchouk, Jana V and Wang, Zhaoming and Yengo, Loic and Zhang, Weihua and Isaacs, Aaron and Albrecht, Eva and Arnl{\"o}v, Johan and Arscott, Gillian M and Attwood, Antony P and Bandinelli, Stefania and Barrett, Amy and Bas, Isabelita N and Bellis, Claire and Bennett, Amanda J and Berne, Christian and Blagieva, Roza and Bl{\"u}her, Matthias and B{\"o}hringer, Stefan and Bonnycastle, Lori L and B{\"o}ttcher, Yvonne and Boyd, Heather A and Bruinenberg, Marcel and Caspersen, Ida H and Ida Chen, Yii-Der and Clarke, Robert and Daw, E Warwick and de Craen, Anton J M and Delgado, Graciela and Dimitriou, Maria and Doney, Alex S F and Eklund, Niina and Estrada, Karol and Eury, Elodie and Folkersen, Lasse and Fraser, Ross M and Garcia, Melissa E and Geller, Frank and Giedraitis, Vilmantas and Gigante, Bruna and Go, Alan S and Golay, Alain and Goodall, Alison H and Gordon, Scott D and Gorski, Mathias and Grabe, Hans-J{\"o}rgen and Grallert, Harald and Grammer, Tanja B and Gr{\"a}{\ss}ler, J{\"u}rgen and Gr{\"o}nberg, Henrik and Groves, Christopher J and Gusto, Ga{\"e}lle and Haessler, Jeffrey and Hall, Per and Haller, Toomas and Hallmans, Goran and Hartman, Catharina A and Hassinen, Maija and Hayward, Caroline and Heard-Costa, Nancy L and Helmer, Quinta and Hengstenberg, Christian and Holmen, Oddgeir and Hottenga, Jouke-Jan and James, Alan L and Jeff, Janina M and Johansson, {\r A}sa and Jolley, Jennifer and Juliusdottir, Thorhildur and Kinnunen, Leena and Koenig, Wolfgang and Koskenvuo, Markku and Kratzer, Wolfgang and Laitinen, Jaana and Lamina, Claudia and Leander, Karin and Lee, Nanette R and Lichtner, Peter and Lind, Lars and Lindstr{\"o}m, Jaana and Sin Lo, Ken and Lobbens, St{\'e}phane and Lorbeer, Roberto and Lu, Yingchang and Mach, Fran{\c c}ois and Magnusson, Patrik K E and Mahajan, Anubha and McArdle, Wendy L and McLachlan, Stela and Menni, Cristina and Merger, Sigrun and Mihailov, Evelin and Milani, Lili and Moayyeri, Alireza and Monda, Keri L and Morken, Mario A and Mulas, Antonella and M{\"u}ller, Gabriele and M{\"u}ller-Nurasyid, Martina and Musk, Arthur W and Nagaraja, Ramaiah and N{\"o}then, Markus M and Nolte, Ilja M and Pilz, Stefan and Rayner, Nigel W and Renstrom, Frida and Rettig, Rainer and Ried, Janina S and Ripke, Stephan and Robertson, Neil R and Rose, Lynda M and Sanna, Serena and Scharnagl, Hubert and Scholtens, Salome and Schumacher, Fredrick R and Scott, William R and Seufferlein, Thomas and Shi, Jianxin and Vernon Smith, Albert and Smolonska, Joanna and Stanton, Alice V and Steinthorsdottir, Valgerdur and Stirrups, Kathleen and Stringham, Heather M and Sundstr{\"o}m, Johan and Swertz, Morris A and Swift, Amy J and Syv{\"a}nen, Ann-Christine and Tan, Sian-Tsung and Tayo, Bamidele O and Thorand, Barbara and Thorleifsson, Gudmar and Tyrer, Jonathan P and Uh, Hae-Won and Vandenput, Liesbeth and Verhulst, Frank C and Vermeulen, Sita H and Verweij, Niek and Vonk, Judith M and Waite, Lindsay L and Warren, Helen R and Waterworth, Dawn and Weedon, Michael N and Wilkens, Lynne R and Willenborg, Christina and Wilsgaard, Tom and Wojczynski, Mary K and Wong, Andrew and Wright, Alan F and Zhang, Qunyuan and Brennan, Eoin P and Choi, Murim and Dastani, Zari and Drong, Alexander W and Eriksson, Per and Franco-Cereceda, Anders and G{\r a}din, Jesper R and Gharavi, Ali G and Goddard, Michael E and Handsaker, Robert E and Huang, Jinyan and Karpe, Fredrik and Kathiresan, Sekar and Keildson, Sarah and Kiryluk, Krzysztof and Kubo, Michiaki and Lee, Jong-Young and Liang, Liming and Lifton, Richard P and Ma, Baoshan and McCarroll, Steven A and McKnight, Amy J and Min, Josine L and Moffatt, Miriam F and Montgomery, Grant W and Murabito, Joanne M and Nicholson, George and Nyholt, Dale R and Okada, Yukinori and Perry, John R B and Dorajoo, Rajkumar and Reinmaa, Eva and Salem, Rany M and Sandholm, Niina and Scott, Robert A and Stolk, Lisette and Takahashi, Atsushi and Tanaka, Toshihiro and Van{\textquoteright}t Hooft, Ferdinand M and Vinkhuyzen, Anna A E and Westra, Harm-Jan and Zheng, Wei and Zondervan, Krina T and Heath, Andrew C and Arveiler, Dominique and Bakker, Stephan J L and Beilby, John and Bergman, Richard N and Blangero, John and Bovet, Pascal and Campbell, Harry and Caulfield, Mark J and Cesana, Giancarlo and Chakravarti, Aravinda and Chasman, Daniel I and Chines, Peter S and Collins, Francis S and Crawford, Dana C and Cupples, L Adrienne and Cusi, Daniele and Danesh, John and de Faire, Ulf and den Ruijter, Hester M and Dominiczak, Anna F and Erbel, Raimund and Erdmann, Jeanette and Eriksson, Johan G and Farrall, Martin and Felix, Stephan B and Ferrannini, Ele and Ferri{\`e}res, Jean and Ford, Ian and Forouhi, Nita G and Forrester, Terrence and Franco, Oscar H and Gansevoort, Ron T and Gejman, Pablo V and Gieger, Christian and Gottesman, Omri and Gudnason, Vilmundur and Gyllensten, Ulf and Hall, Alistair S and Harris, Tamara B and Hattersley, Andrew T and Hicks, Andrew A and Hindorff, Lucia A and Hingorani, Aroon D and Hofman, Albert and Homuth, Georg and Hovingh, G Kees and Humphries, Steve E and Hunt, Steven C and Hypp{\"o}nen, Elina and Illig, Thomas and Jacobs, Kevin B and J{\"a}rvelin, Marjo-Riitta and J{\"o}ckel, Karl-Heinz and Johansen, Berit and Jousilahti, Pekka and Jukema, J Wouter and Jula, Antti M and Kaprio, Jaakko and Kastelein, John J P and Keinanen-Kiukaanniemi, Sirkka M and Kiemeney, Lambertus A and Knekt, Paul and Kooner, Jaspal S and Kooperberg, Charles and Kovacs, Peter and Kraja, Aldi T and Kumari, Meena and Kuusisto, Johanna and Lakka, Timo A and Langenberg, Claudia and Le Marchand, Loic and Lehtim{\"a}ki, Terho and Lyssenko, Valeriya and M{\"a}nnist{\"o}, Satu and Marette, Andr{\'e} and Matise, Tara C and McKenzie, Colin A and McKnight, Barbara and Moll, Frans L and Morris, Andrew D and Morris, Andrew P and Murray, Jeffrey C and Nelis, Mari and Ohlsson, Claes and Oldehinkel, Albertine J and Ong, Ken K and Madden, Pamela A F and Pasterkamp, Gerard and Peden, John F and Peters, Annette and Postma, Dirkje S and Pramstaller, Peter P and Price, Jackie F and Qi, Lu and Raitakari, Olli T and Rankinen, Tuomo and Rao, D C and Rice, Treva K and Ridker, Paul M and Rioux, John D and Ritchie, Marylyn D and Rudan, Igor and Salomaa, Veikko and Samani, Nilesh J and Saramies, Jouko and Sarzynski, Mark A and Schunkert, Heribert and Schwarz, Peter E H and Sever, Peter and Shuldiner, Alan R and Sinisalo, Juha and Stolk, Ronald P and Strauch, Konstantin and T{\"o}njes, Anke and Tr{\'e}gou{\"e}t, David-Alexandre and Tremblay, Angelo and Tremoli, Elena and Virtamo, Jarmo and Vohl, Marie-Claude and V{\"o}lker, Uwe and Waeber, Gerard and Willemsen, Gonneke and Witteman, Jacqueline C and Zillikens, M Carola and Adair, Linda S and Amouyel, Philippe and Asselbergs, Folkert W and Assimes, Themistocles L and Bochud, Murielle and Boehm, Bernhard O and Boerwinkle, Eric and Bornstein, Stefan R and Bottinger, Erwin P and Bouchard, Claude and Cauchi, St{\'e}phane and Chambers, John C and Chanock, Stephen J and Cooper, Richard S and de Bakker, Paul I W and Dedoussis, George and Ferrucci, Luigi and Franks, Paul W and Froguel, Philippe and Groop, Leif C and Haiman, Christopher A and Hamsten, Anders and Hui, Jennie and Hunter, David J and Hveem, Kristian and Kaplan, Robert C and Kivimaki, Mika and Kuh, Diana and Laakso, Markku and Liu, Yongmei and Martin, Nicholas G and M{\"a}rz, Winfried and Melbye, Mads and Metspalu, Andres and Moebus, Susanne and Munroe, Patricia B and Nj{\o}lstad, Inger and Oostra, Ben A and Palmer, Colin N A and Pedersen, Nancy L and Perola, Markus and P{\'e}russe, Louis and Peters, Ulrike and Power, Chris and Quertermous, Thomas and Rauramaa, Rainer and Rivadeneira, Fernando and Saaristo, Timo E and Saleheen, Danish and Sattar, Naveed and Schadt, Eric E and Schlessinger, David and Slagboom, P Eline and Snieder, Harold and Spector, Tim D and Thorsteinsdottir, Unnur and Stumvoll, Michael and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Uusitupa, Matti and van der Harst, Pim and Walker, Mark and Wallaschofski, Henri and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wichmann, H-Erich and Wilson, James F and Zanen, Pieter and Borecki, Ingrid B and Deloukas, Panos and Fox, Caroline S and Heid, Iris M and O{\textquoteright}Connell, Jeffrey R and Strachan, David P and Stefansson, Kari and van Duijn, Cornelia M and Abecasis, Goncalo R and Franke, Lude and Frayling, Timothy M and McCarthy, Mark I and Visscher, Peter M and Scherag, Andr{\'e} and Willer, Cristen J and Boehnke, Michael and Mohlke, Karen L and Lindgren, Cecilia M and Beckmann, Jacques S and Barroso, In{\^e}s and North, Kari E and Ingelsson, Erik and Hirschhorn, Joel N and Loos, Ruth J F and Speliotes, Elizabeth K} } @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 {7692, title = {New genetic loci link adipose and insulin biology to body fat distribution.}, journal = {Nature}, volume = {518}, year = {2015}, month = {2015 Feb 12}, pages = {187-96}, abstract = {

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P~<~5~{\texttimes}~10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

}, keywords = {Adipocytes, Adipogenesis, Adipose Tissue, Age Factors, Body Fat Distribution, Body Mass Index, Continental Population Groups, Epigenesis, Genetic, Europe, Female, Genome, Human, Genome-Wide Association Study, Humans, Insulin, Insulin Resistance, Male, Models, Biological, Neovascularization, Physiologic, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Sex Characteristics, Transcription, Genetic, Waist-Hip Ratio}, issn = {1476-4687}, doi = {10.1038/nature14132}, author = {Shungin, Dmitry and Winkler, Thomas W and Croteau-Chonka, Damien C and Ferreira, Teresa and Locke, Adam E and M{\"a}gi, Reedik and Strawbridge, Rona J and Pers, Tune H and Fischer, Krista and Justice, Anne E and Workalemahu, Tsegaselassie and Wu, Joseph M W and Buchkovich, Martin L and Heard-Costa, Nancy L and Roman, Tamara S and Drong, Alexander W and Song, Ci and Gustafsson, Stefan and Day, Felix R and Esko, T{\~o}nu and Fall, Tove and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and Randall, Joshua C and Scherag, Andr{\'e} and Vedantam, Sailaja and Wood, Andrew R and Chen, Jin and Fehrmann, Rudolf and Karjalainen, Juha and Kahali, Bratati and Liu, Ching-Ti and Schmidt, Ellen M and Absher, Devin and Amin, Najaf and Anderson, Denise and Beekman, Marian and Bragg-Gresham, Jennifer L and Buyske, Steven and Demirkan, Ayse and Ehret, Georg B and Feitosa, Mary F and Goel, Anuj and Jackson, Anne U and Johnson, Toby and Kleber, Marcus E and Kristiansson, Kati and Mangino, Massimo and Mateo Leach, Irene and Medina-Gomez, Carolina and Palmer, Cameron D and Pasko, Dorota and Pechlivanis, Sonali and Peters, Marjolein J and Prokopenko, Inga and Stan{\v c}{\'a}kov{\'a}, Alena and Ju Sung, Yun and Tanaka, Toshiko and Teumer, Alexander and Van Vliet-Ostaptchouk, Jana V and Yengo, Loic and Zhang, Weihua and Albrecht, Eva and Arnl{\"o}v, Johan and Arscott, Gillian M and Bandinelli, Stefania and Barrett, Amy and Bellis, Claire and Bennett, Amanda J and Berne, Christian and Bl{\"u}her, Matthias and B{\"o}hringer, Stefan and Bonnet, Fabrice and B{\"o}ttcher, Yvonne and Bruinenberg, Marcel and Carba, Delia B and Caspersen, Ida H and Clarke, Robert and Daw, E Warwick and Deelen, Joris and Deelman, Ewa and Delgado, Graciela and Doney, Alex S F and Eklund, Niina and Erdos, Michael R and Estrada, Karol and Eury, Elodie and Friedrich, Nele and Garcia, Melissa E and Giedraitis, Vilmantas and Gigante, Bruna and Go, Alan S and Golay, Alain and Grallert, Harald and Grammer, Tanja B and Gr{\"a}{\ss}ler, J{\"u}rgen and Grewal, Jagvir and Groves, Christopher J and Haller, Toomas and Hallmans, Goran and Hartman, Catharina A and Hassinen, Maija and Hayward, Caroline and Heikkil{\"a}, Kauko and Herzig, Karl-Heinz and Helmer, Quinta and Hillege, Hans L and Holmen, Oddgeir and Hunt, Steven C and Isaacs, Aaron and Ittermann, Till and James, Alan L and Johansson, Ingegerd and Juliusdottir, Thorhildur and Kalafati, Ioanna-Panagiota and Kinnunen, Leena and Koenig, Wolfgang and Kooner, Ishminder K and Kratzer, Wolfgang and Lamina, Claudia and Leander, Karin and Lee, Nanette R and Lichtner, Peter and Lind, Lars and Lindstr{\"o}m, Jaana and Lobbens, St{\'e}phane and Lorentzon, Mattias and Mach, Fran{\c c}ois and Magnusson, Patrik K E and Mahajan, Anubha and McArdle, Wendy L and Menni, Cristina and Merger, Sigrun and Mihailov, Evelin and Milani, Lili and Mills, Rebecca and Moayyeri, Alireza and Monda, Keri L and Mooijaart, Simon P and M{\"u}hleisen, Thomas W and Mulas, Antonella and M{\"u}ller, Gabriele and M{\"u}ller-Nurasyid, Martina and Nagaraja, Ramaiah and Nalls, Michael A and Narisu, Narisu and Glorioso, Nicola and Nolte, Ilja M and Olden, Matthias and Rayner, Nigel W and Renstrom, Frida and Ried, Janina S and Robertson, Neil R and Rose, Lynda M and Sanna, Serena and Scharnagl, Hubert and Scholtens, Salome and Sennblad, Bengt and Seufferlein, Thomas and Sitlani, Colleen M and Vernon Smith, Albert and Stirrups, Kathleen and Stringham, Heather M and Sundstr{\"o}m, Johan and Swertz, Morris A and Swift, Amy J and Syv{\"a}nen, Ann-Christine and Tayo, Bamidele O and Thorand, Barbara and Thorleifsson, Gudmar and Tomaschitz, Andreas and Troffa, Chiara and van Oort, Floor V A and Verweij, Niek and Vonk, Judith M and Waite, Lindsay L and Wennauer, Roman and Wilsgaard, Tom and Wojczynski, Mary K and Wong, Andrew and Zhang, Qunyuan and Hua Zhao, Jing and Brennan, Eoin P and Choi, Murim and Eriksson, Per and Folkersen, Lasse and Franco-Cereceda, Anders and Gharavi, Ali G and Hedman, {\r A}sa K and Hivert, Marie-France and Huang, Jinyan and Kanoni, Stavroula and Karpe, Fredrik and Keildson, Sarah and Kiryluk, Krzysztof and Liang, Liming and Lifton, Richard P and Ma, Baoshan and McKnight, Amy J and McPherson, Ruth and Metspalu, Andres and Min, Josine L and Moffatt, Miriam F and Montgomery, Grant W and Murabito, Joanne M and Nicholson, George and Nyholt, Dale R and Olsson, Christian and Perry, John R B and Reinmaa, Eva and Salem, Rany M and Sandholm, Niina and Schadt, Eric E and Scott, Robert A and Stolk, Lisette and Vallejo, Edgar E and Westra, Harm-Jan and Zondervan, Krina T and Amouyel, Philippe and Arveiler, Dominique and Bakker, Stephan J L and Beilby, John and Bergman, Richard N and Blangero, John and Brown, Morris J and Burnier, Michel and Campbell, Harry and Chakravarti, Aravinda and Chines, Peter S and Claudi-Boehm, Simone and Collins, Francis S and Crawford, Dana C and Danesh, John and de Faire, Ulf and de Geus, Eco J C and D{\"o}rr, Marcus and Erbel, Raimund and Eriksson, Johan G and Farrall, Martin and Ferrannini, Ele and Ferri{\`e}res, Jean and Forouhi, Nita G and Forrester, Terrence and Franco, Oscar H and Gansevoort, Ron T and Gieger, Christian and Gudnason, Vilmundur and Haiman, Christopher A and Harris, Tamara B and Hattersley, Andrew T and Heli{\"o}vaara, Markku and Hicks, Andrew A and Hingorani, Aroon D and Hoffmann, Wolfgang and Hofman, Albert and Homuth, Georg and Humphries, Steve E and Hypp{\"o}nen, Elina and Illig, Thomas and J{\"a}rvelin, Marjo-Riitta and Johansen, Berit and Jousilahti, Pekka and Jula, Antti M and Kaprio, Jaakko and Kee, Frank and Keinanen-Kiukaanniemi, Sirkka M and Kooner, Jaspal S and Kooperberg, Charles and Kovacs, Peter and Kraja, Aldi T and Kumari, Meena and Kuulasmaa, Kari and Kuusisto, Johanna and Lakka, Timo A and Langenberg, Claudia and Le Marchand, Loic and Lehtim{\"a}ki, Terho and Lyssenko, Valeriya and M{\"a}nnist{\"o}, Satu and Marette, Andr{\'e} and Matise, Tara C and McKenzie, Colin A and McKnight, Barbara and Musk, Arthur W and M{\"o}hlenkamp, Stefan and Morris, Andrew D and Nelis, Mari and Ohlsson, Claes and Oldehinkel, Albertine J and Ong, Ken K and Palmer, Lyle J and Penninx, Brenda W and Peters, Annette and Pramstaller, Peter P and Raitakari, Olli T and Rankinen, Tuomo and Rao, D C and Rice, Treva K and Ridker, Paul M and Ritchie, Marylyn D and Rudan, Igor and Salomaa, Veikko and Samani, Nilesh J and Saramies, Jouko and Sarzynski, Mark A and Schwarz, Peter E H and Shuldiner, Alan R and Staessen, Jan A and Steinthorsdottir, Valgerdur and Stolk, Ronald P and Strauch, Konstantin and T{\"o}njes, Anke and Tremblay, Angelo and Tremoli, Elena and Vohl, Marie-Claude and V{\"o}lker, Uwe and Vollenweider, Peter and Wilson, James F and Witteman, Jacqueline C and Adair, Linda S and Bochud, Murielle and Boehm, Bernhard O and Bornstein, Stefan R and Bouchard, Claude and Cauchi, St{\'e}phane and Caulfield, Mark J and Chambers, John C and Chasman, Daniel I and Cooper, Richard S and Dedoussis, George and Ferrucci, Luigi and Froguel, Philippe and Grabe, Hans-J{\"o}rgen and Hamsten, Anders and Hui, Jennie and Hveem, Kristian and J{\"o}ckel, Karl-Heinz and Kivimaki, Mika and Kuh, Diana and Laakso, Markku and Liu, Yongmei and M{\"a}rz, Winfried and Munroe, Patricia B and Nj{\o}lstad, Inger and Oostra, Ben A and Palmer, Colin N A and Pedersen, Nancy L and Perola, Markus and P{\'e}russe, Louis and Peters, Ulrike and Power, Chris and Quertermous, Thomas and Rauramaa, Rainer and Rivadeneira, Fernando and Saaristo, Timo E and Saleheen, Danish and Sinisalo, Juha and Slagboom, P Eline and Snieder, Harold and Spector, Tim D and Thorsteinsdottir, Unnur and Stumvoll, Michael and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Uusitupa, Matti and van der Harst, Pim and Veronesi, Giovanni and Walker, Mark and Wareham, Nicholas J and Watkins, Hugh and Wichmann, H-Erich and Abecasis, Goncalo R and Assimes, Themistocles L and Berndt, Sonja I and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and Franke, Lude and Frayling, Timothy M and Groop, Leif C and Hunter, David J and Kaplan, Robert C and O{\textquoteright}Connell, Jeffrey R and Qi, Lu and Schlessinger, David and Strachan, David P and Stefansson, Kari and van Duijn, Cornelia M and Willer, Cristen J and Visscher, Peter M and Yang, Jian and Hirschhorn, Joel N and Zillikens, M Carola and McCarthy, Mark I and Speliotes, Elizabeth K and North, Kari E and Fox, Caroline S and Barroso, In{\^e}s and Franks, Paul W and Ingelsson, Erik and Heid, Iris M and Loos, Ruth J F and Cupples, L Adrienne and Morris, Andrew P and Lindgren, Cecilia M and Mohlke, Karen L} } @article {8039, title = {Population genetic differentiation of height and body mass index across Europe.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Nov}, pages = {1357-62}, abstract = {

Across-nation differences in the mean values for complex traits are common, but the reasons for these differences are unknown. Here we find that many independent loci contribute to population genetic differences in height and body mass index (BMI) in 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling pairs, we estimate that 24\% (95\% credible interval (CI) = 9\%, 41\%) and 8\% (95\% CI = 4\%, 16\%) of the captured additive genetic variance for height and BMI, respectively, reflect population genetic differences. Population genetic divergence differed significantly from that in a null model (height, P < 3.94 {\texttimes} 10(-8); BMI, P < 5.95 {\texttimes} 10(-4)), and we find an among-population genetic correlation for tall and slender individuals (r = -0.80, 95\% CI = -0.95, -0.60), consistent with correlated selection for both phenotypes. Observed differences in height among populations reflected the predicted genetic means (r = 0.51; P < 0.001), but environmental differences across Europe masked genetic differentiation for BMI (P < 0.58).

}, issn = {1546-1718}, doi = {10.1038/ng.3401}, author = {Robinson, Matthew R and Hemani, Gibran and Medina-Gomez, Carolina and Mezzavilla, Massimo and Esko, T{\~o}nu and Shakhbazov, Konstantin and Powell, Joseph E and Vinkhuyzen, Anna and Berndt, Sonja I and Gustafsson, Stefan and Justice, Anne E and Kahali, Bratati and Locke, Adam E and Pers, Tune H and Vedantam, Sailaja and Wood, Andrew R and van Rheenen, Wouter and Andreassen, Ole A and Gasparini, Paolo and Metspalu, Andres and Berg, Leonard H van den and Veldink, Jan H and Rivadeneira, Fernando and Werge, Thomas M and Abecasis, Goncalo R and Boomsma, Dorret I and Chasman, Daniel I and de Geus, Eco J C and Frayling, Timothy M and Hirschhorn, Joel N and Hottenga, Jouke Jan and Ingelsson, Erik and Loos, Ruth J F and Magnusson, Patrik K E and Martin, Nicholas G and Montgomery, Grant W and North, Kari E and Pedersen, Nancy L and Spector, Timothy D and Speliotes, Elizabeth K and Goddard, Michael E and Yang, Jian and Visscher, Peter M} } @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 {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 {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 {1734, title = {Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Dec}, pages = {1077-85}, abstract = {

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 {\texttimes} 10$^{-}$$^{6}$$^{0}$) and 9q31.2 (P = 2.2 {\texttimes} 10$^{-}${\textthreesuperior}{\textthreesuperior}), we identified 30 new menarche loci (all P < 5 {\texttimes} 10$^{-}$$^{8}$) and found suggestive evidence for a further 10 loci (P < 1.9 {\texttimes} 10$^{-}$$^{6}$). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

}, keywords = {Adolescent, Aging, Body Height, Body Size, Child, DNA Copy Number Variations, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inheritance Patterns, Menarche, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Reproducibility of Results, Time Factors}, issn = {1546-1718}, doi = {10.1038/ng.714}, author = {Elks, Cathy E and Perry, John R B and Sulem, Patrick and Chasman, Daniel I and Franceschini, Nora and He, Chunyan and Lunetta, Kathryn L and Visser, Jenny A and Byrne, Enda M and Cousminer, Diana L and Gudbjartsson, Daniel F and Esko, T{\~o}nu and Feenstra, Bjarke and Hottenga, Jouke-Jan and Koller, Daniel L and Kutalik, Zolt{\'a}n and Lin, Peng and Mangino, Massimo and Marongiu, Mara and McArdle, Patrick F and Smith, Albert V and Stolk, Lisette and van Wingerden, Sophie H and Zhao, Jing Hua and Albrecht, Eva and Corre, Tanguy and Ingelsson, Erik and Hayward, Caroline and Magnusson, Patrik K E and Smith, Erin N and Ulivi, Shelia and Warrington, Nicole M and Zgaga, Lina and Alavere, Helen and Amin, Najaf and Aspelund, Thor and Bandinelli, Stefania and Barroso, In{\^e}s and Berenson, Gerald S and Bergmann, Sven and Blackburn, Hannah and Boerwinkle, Eric and Buring, Julie E and Busonero, Fabio and Campbell, Harry and Chanock, Stephen J and Chen, Wei and Cornelis, Marilyn C and Couper, David and Coviello, Andrea D and d{\textquoteright}Adamo, Pio and de Faire, Ulf and de Geus, Eco J C and Deloukas, Panos and D{\"o}ring, Angela and Smith, George Davey and Easton, Douglas F and Eiriksdottir, Gudny and Emilsson, Valur and Eriksson, Johan and Ferrucci, Luigi and Folsom, Aaron R and Foroud, Tatiana and Garcia, Melissa and Gasparini, Paolo and Geller, Frank and Gieger, Christian and Gudnason, Vilmundur and Hall, Per and Hankinson, Susan E and Ferreli, Liana and Heath, Andrew C and Hernandez, Dena G and Hofman, Albert and Hu, Frank B and Illig, Thomas and J{\"a}rvelin, Marjo-Riitta and Johnson, Andrew D and Karasik, David and Khaw, Kay-Tee and Kiel, Douglas P and Kilpel{\"a}inen, Tuomas O and Kolcic, Ivana and Kraft, Peter and Launer, Lenore J and Laven, Joop S E and Li, Shengxu and Liu, Jianjun and Levy, Daniel and Martin, Nicholas G and McArdle, Wendy L and Melbye, Mads and Mooser, Vincent and Murray, Jeffrey C and Murray, Sarah S and Nalls, Michael A and Navarro, Pau and Nelis, Mari and Ness, Andrew R and Northstone, Kate and Oostra, Ben A and Peacock, Munro and Palmer, Lyle J and Palotie, Aarno and Par{\'e}, Guillaume and Parker, Alex N and Pedersen, Nancy L and Peltonen, Leena and Pennell, Craig E and Pharoah, Paul and Polasek, Ozren and Plump, Andrew S and Pouta, Anneli and Porcu, Eleonora and Rafnar, Thorunn and Rice, John P and Ring, Susan M and Rivadeneira, Fernando and Rudan, Igor and Sala, Cinzia and Salomaa, Veikko and Sanna, Serena and Schlessinger, David and Schork, Nicholas J and Scuteri, Angelo and Segr{\`e}, Ayellet V and Shuldiner, Alan R and Soranzo, Nicole and Sovio, Ulla and Srinivasan, Sathanur R and Strachan, David P and Tammesoo, Mar-Liis and Tikkanen, Emmi and Toniolo, Daniela and Tsui, Kim and Tryggvadottir, Laufey and Tyrer, Jonathon and Uda, Manuela and van Dam, Rob M and van Meurs, Joyce B J and Vollenweider, Peter and Waeber, Gerard and Wareham, Nicholas J and Waterworth, Dawn M and Weedon, Michael N and Wichmann, H Erich and Willemsen, Gonneke and Wilson, James F and Wright, Alan F and Young, Lauren and Zhai, Guangju and Zhuang, Wei Vivian and Bierut, Laura J and Boomsma, Dorret I and Boyd, Heather A and Crisponi, Laura and Demerath, Ellen W and van Duijn, Cornelia M and Econs, Michael J and Harris, Tamara B and Hunter, David J and Loos, Ruth J F and Metspalu, Andres and Montgomery, Grant W and Ridker, Paul M and Spector, Tim D and Streeten, Elizabeth A and Stefansson, Kari and Thorsteinsdottir, Unnur and Uitterlinden, Andr{\'e} G and Widen, Elisabeth and Murabito, Joanne M and Ong, Ken K and Murray, Anna} }