TY - JOUR T1 - Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. JF - Genome Biol Y1 - 2018 A1 - Prins, Bram P A1 - Mead, Timothy J A1 - Brody, Jennifer A A1 - Sveinbjornsson, Gardar A1 - Ntalla, Ioanna A1 - Bihlmeyer, Nathan A A1 - van den Berg, Marten A1 - Bork-Jensen, Jette A1 - Cappellani, Stefania A1 - Van Duijvenboden, Stefan A1 - Klena, Nikolai T A1 - Gabriel, George C A1 - Liu, Xiaoqin A1 - Gulec, Cagri A1 - Grarup, Niels A1 - Haessler, Jeffrey A1 - Hall, Leanne M A1 - Iorio, Annamaria A1 - Isaacs, Aaron A1 - Li-Gao, Ruifang A1 - Lin, Honghuang A1 - Liu, Ching-Ti A1 - Lyytikäinen, Leo-Pekka A1 - Marten, Jonathan A1 - Mei, Hao A1 - Müller-Nurasyid, Martina A1 - Orini, Michele A1 - Padmanabhan, Sandosh A1 - Radmanesh, Farid A1 - Ramirez, Julia A1 - Robino, Antonietta A1 - Schwartz, Molly A1 - van Setten, Jessica A1 - Smith, Albert V A1 - Verweij, Niek A1 - Warren, Helen R A1 - Weiss, Stefan A1 - Alonso, Alvaro A1 - Arnar, David O A1 - Bots, Michiel L A1 - de Boer, Rudolf A A1 - Dominiczak, Anna F A1 - Eijgelsheim, Mark A1 - Ellinor, Patrick T A1 - Guo, Xiuqing A1 - Felix, Stephan B A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Huang, Paul L A1 - Jukema, J W A1 - Kähönen, Mika A1 - Kors, Jan A A1 - Lambiase, Pier D A1 - Launer, Lenore J A1 - Li, Man A1 - Linneberg, Allan A1 - Nelson, Christopher P A1 - Pedersen, Oluf A1 - Perez, Marco A1 - Peters, Annette A1 - Polasek, Ozren A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Rice, Kenneth M A1 - Rotter, Jerome I A1 - Sinner, Moritz F A1 - Soliman, Elsayed Z A1 - Spector, Tim D A1 - Strauch, Konstantin A1 - Thorsteinsdottir, Unnur A1 - Tinker, Andrew A1 - Trompet, Stella A1 - Uitterlinden, André A1 - Vaartjes, Ilonca A1 - van der Meer, Peter A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wilson, James G A1 - Xie, Zhijun A1 - Asselbergs, Folkert W A1 - Dörr, Marcus A1 - van Duijn, Cornelia M A1 - Gasparini, Paolo A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Kääb, Stefan A1 - Kanters, Jørgen K A1 - Kooperberg, Charles A1 - Lehtimäki, Terho A1 - Lin, Henry J A1 - Lubitz, Steven A A1 - Mook-Kanamori, Dennis O A1 - Conti, Francesco J A1 - Newton-Cheh, Christopher H A1 - Rosand, Jonathan A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Sinagra, Gianfranco A1 - Smith, Blair H A1 - Holm, Hilma A1 - Stricker, Bruno H A1 - Ulivi, Sheila A1 - Sotoodehnia, Nona A1 - Apte, Suneel S A1 - van der Harst, Pim A1 - Stefansson, Kari A1 - Munroe, Patricia B A1 - Arking, Dan E A1 - Lo, Cecilia W A1 - Jamshidi, Yalda KW - ADAMTS Proteins KW - African Continental Ancestry Group KW - Animals KW - Connexin 43 KW - Electrocardiography KW - European Continental Ancestry Group KW - Exome KW - Female KW - Gene Expression KW - Gene Expression Profiling KW - Genetic Loci KW - Genome-Wide Association Study KW - Heart Conduction System KW - Humans KW - Male KW - Mice KW - Middle Aged KW - Myocardium KW - Open Reading Frames KW - Polymorphism, Single Nucleotide KW - Whole Exome Sequencing AB -

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

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

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

VL - 19 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30012220?dopt=Abstract ER - TY - JOUR T1 - 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function. JF - Sci Rep Y1 - 2017 A1 - Gorski, Mathias A1 - van der Most, Peter J A1 - Teumer, Alexander A1 - Chu, Audrey Y A1 - Li, Man A1 - Mijatovic, Vladan A1 - Nolte, Ilja M A1 - Cocca, Massimiliano A1 - Taliun, Daniel A1 - Gomez, Felicia A1 - Li, Yong A1 - Tayo, Bamidele A1 - Tin, Adrienne A1 - Feitosa, Mary F A1 - Aspelund, Thor A1 - Attia, John A1 - Biffar, Reiner A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Borecki, Ingrid A1 - Bottinger, Erwin P A1 - Chen, Ming-Huei A1 - Chouraki, Vincent A1 - Ciullo, Marina A1 - Coresh, Josef A1 - Cornelis, Marilyn C A1 - Curhan, Gary C A1 - d'Adamo, Adamo Pio A1 - Dehghan, Abbas A1 - Dengler, Laura A1 - Ding, Jingzhong A1 - Eiriksdottir, Gudny A1 - Endlich, Karlhans A1 - Enroth, Stefan A1 - Esko, Tõnu A1 - Franco, Oscar H A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Gottesman, Omri A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hancock, Stephen J A1 - Harris, Tamara B A1 - Helmer, Catherine A1 - Höllerer, Simon A1 - Hofer, Edith A1 - Hofman, Albert A1 - Holliday, Elizabeth G A1 - Homuth, Georg A1 - Hu, Frank B A1 - Huth, Cornelia A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Imboden, Medea A1 - Johansson, Åsa A1 - Kähönen, Mika A1 - König, Wolfgang A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kumar, Ashish A1 - Kutalik, Zoltán A1 - Lambert, Jean-Charles A1 - Launer, Lenore J A1 - Lehtimäki, Terho A1 - de Borst, Martin A1 - Navis, Gerjan A1 - Swertz, Morris A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Loos, Ruth J F A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - McEvoy, Mark A A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Metzger, Marie A1 - Mihailov, Evelin A1 - Mitchell, Paul A1 - Nauck, Matthias A1 - Oldehinkel, Albertine J A1 - Olden, Matthias A1 - Wjh Penninx, Brenda A1 - Pistis, Giorgio A1 - Pramstaller, Peter P A1 - Probst-Hensch, Nicole A1 - Raitakari, Olli T A1 - Rettig, Rainer A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Robino, Antonietta A1 - Rosas, Sylvia E A1 - Ruderfer, Douglas A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Sala, Cinzia A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Scott, Rodney J A1 - Sedaghat, Sanaz A1 - Smith, Albert V A1 - Sorice, Rossella A1 - Stengel, Bénédicte A1 - Stracke, Sylvia A1 - Strauch, Konstantin A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Viikari, Jorma S A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Vuckovic, Dragana A1 - Waldenberger, Melanie A1 - Jin Wang, Jie A1 - Yang, Qiong A1 - Chasman, Daniel I A1 - Tromp, Gerard A1 - Snieder, Harold A1 - Heid, Iris M A1 - Fox, Caroline S A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Böger, Carsten A A1 - Fuchsberger, Christian KW - Computational Biology KW - Gene Frequency KW - Genetic Loci KW - Genome, Human KW - Genome-Wide Association Study KW - Genotyping Techniques KW - Humans KW - Kidney KW - Polymorphism, Single Nucleotide AB -

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 × 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.

VL - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28452372?dopt=Abstract ER - TY - JOUR T1 - and Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. JF - J Am Soc Nephrol Y1 - 2017 A1 - Li, Man A1 - Li, Yong A1 - Weeks, Olivia A1 - Mijatovic, Vladan A1 - Teumer, Alexander A1 - Huffman, Jennifer E A1 - Tromp, Gerard A1 - Fuchsberger, Christian A1 - Gorski, Mathias A1 - Lyytikäinen, Leo-Pekka A1 - Nutile, Teresa A1 - Sedaghat, Sanaz A1 - Sorice, Rossella A1 - Tin, Adrienne A1 - Yang, Qiong A1 - Ahluwalia, Tarunveer S A1 - Arking, Dan E A1 - Bihlmeyer, Nathan A A1 - Böger, Carsten A A1 - Carroll, Robert J A1 - Chasman, Daniel I A1 - Cornelis, Marilyn C A1 - Dehghan, Abbas A1 - Faul, Jessica D A1 - Feitosa, Mary F A1 - Gambaro, Giovanni A1 - Gasparini, Paolo A1 - Giulianini, Franco A1 - Heid, Iris A1 - Huang, Jinyan A1 - Imboden, Medea A1 - Jackson, Anne U A1 - Jeff, Janina A1 - Jhun, Min A A1 - Katz, Ronit A1 - Kifley, Annette A1 - Kilpeläinen, Tuomas O A1 - Kumar, Ashish A1 - Laakso, Markku A1 - Li-Gao, Ruifang A1 - Lohman, Kurt A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Malerba, Giovanni A1 - Mihailov, Evelin A1 - Mohlke, Karen L A1 - Mook-Kanamori, Dennis O A1 - Robino, Antonietta A1 - Ruderfer, Douglas A1 - Salvi, Erika A1 - Schick, Ursula M A1 - Schulz, Christina-Alexandra A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Traglia, Michela A1 - Yerges-Armstrong, Laura M A1 - Zhao, Wei A1 - Goodarzi, Mark O A1 - Kraja, Aldi T A1 - Liu, Chunyu A1 - Wessel, Jennifer A1 - Boerwinkle, Eric A1 - Borecki, Ingrid B A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Braga, Daniele A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Carey, David J A1 - Christensen, Cramer A1 - Coresh, Josef A1 - Crook, Errol A1 - Curhan, Gary C A1 - Cusi, Daniele A1 - de Boer, Ian H A1 - de Vries, Aiko P J A1 - Denny, Joshua C A1 - Devuyst, Olivier A1 - Dreisbach, Albert W A1 - Endlich, Karlhans A1 - Esko, Tõnu A1 - Franco, Oscar H A1 - Fulop, Tibor A1 - Gerhard, Glenn S A1 - Glümer, Charlotte A1 - Gottesman, Omri A1 - Grarup, Niels A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hocking, Lynne A1 - Hofman, Albert A1 - Hu, Frank B A1 - Husemoen, Lise Lotte N A1 - Jackson, Rebecca D A1 - Jørgensen, Torben A1 - Jørgensen, Marit E A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - König, Wolfgang A1 - Kooperberg, Charles A1 - Kriebel, Jennifer A1 - Launer, Lenore J A1 - Lauritzen, Torsten A1 - Lehtimäki, Terho A1 - Levy, Daniel A1 - Linksted, Pamela A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lupo, Antonio A1 - Meisinger, Christine A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mitchell, Paul A1 - Nauck, Matthias A1 - Nürnberg, Peter A1 - Orho-Melander, Marju A1 - Parsa, Afshin A1 - Pedersen, Oluf A1 - Peters, Annette A1 - Peters, Ulrike A1 - Polasek, Ozren A1 - Porteous, David A1 - Probst-Hensch, Nicole M A1 - Psaty, Bruce M A1 - Qi, Lu A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rettig, Rainer A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rossouw, Jacques E A1 - Schmidt, Frank A1 - Siscovick, David A1 - Soranzo, Nicole A1 - Strauch, Konstantin A1 - Toniolo, Daniela A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Velayutham, Dinesh A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wang, Jie Jin A1 - Weir, David R A1 - Witte, Daniel A1 - Kuivaniemi, Helena A1 - Fox, Caroline S A1 - Franceschini, Nora A1 - Goessling, Wolfram A1 - Köttgen, Anna A1 - Chu, Audrey Y KW - Animals KW - Exome KW - Genetic Loci KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Protein Tyrosine Phosphatases KW - Proto-Oncogene Proteins KW - Son of Sevenless Proteins KW - Zebrafish AB -

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 ; <3.7×10), 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, (=5.4×10 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.

VL - 28 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27920155?dopt=Abstract ER - TY - JOUR T1 - Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. JF - Nat Commun Y1 - 2016 A1 - Pattaro, Cristian A1 - Teumer, Alexander A1 - Gorski, Mathias A1 - Chu, Audrey Y A1 - Li, Man A1 - Mijatovic, Vladan A1 - Garnaas, Maija A1 - Tin, Adrienne A1 - Sorice, Rossella A1 - Li, Yong A1 - Taliun, Daniel A1 - Olden, Matthias A1 - Foster, Meredith A1 - Yang, Qiong A1 - Chen, Ming-Huei A1 - Pers, Tune H A1 - Johnson, Andrew D A1 - Ko, Yi-An A1 - Fuchsberger, Christian A1 - Tayo, Bamidele A1 - Nalls, Michael A1 - Feitosa, Mary F A1 - Isaacs, Aaron A1 - Dehghan, Abbas A1 - d'Adamo, Pio A1 - Adeyemo, Adebowale A1 - Dieffenbach, Aida Karina A1 - Zonderman, Alan B A1 - Nolte, Ilja M A1 - van der Most, Peter J A1 - Wright, Alan F A1 - Shuldiner, Alan R A1 - Morrison, Alanna C A1 - Hofman, Albert A1 - Smith, Albert V A1 - Dreisbach, Albert W A1 - Franke, Andre A1 - Uitterlinden, André G A1 - Metspalu, Andres A1 - Tönjes, Anke A1 - Lupo, Antonio A1 - Robino, Antonietta A1 - Johansson, Åsa A1 - Demirkan, Ayse A1 - Kollerits, Barbara A1 - Freedman, Barry I A1 - Ponte, Belen A1 - Oostra, Ben A A1 - Paulweber, Bernhard A1 - Krämer, Bernhard K A1 - Mitchell, Braxton D A1 - Buckley, Brendan M A1 - Peralta, Carmen A A1 - Hayward, Caroline A1 - Helmer, Catherine A1 - Rotimi, Charles N A1 - Shaffer, Christian M A1 - Müller, Christian A1 - Sala, Cinzia A1 - van Duijn, Cornelia M A1 - Saint-Pierre, Aude A1 - Ackermann, Daniel A1 - Shriner, Daniel A1 - Ruggiero, Daniela A1 - Toniolo, Daniela A1 - Lu, Yingchang A1 - Cusi, Daniele A1 - Czamara, Darina A1 - Ellinghaus, David A1 - Siscovick, David S A1 - Ruderfer, Douglas A1 - Gieger, Christian A1 - Grallert, Harald A1 - Rochtchina, Elena A1 - Atkinson, Elizabeth J A1 - Holliday, Elizabeth G A1 - Boerwinkle, Eric A1 - Salvi, Erika A1 - Bottinger, Erwin P A1 - Murgia, Federico A1 - Rivadeneira, Fernando A1 - Ernst, Florian A1 - Kronenberg, Florian A1 - Hu, Frank B A1 - Navis, Gerjan J A1 - Curhan, Gary C A1 - Ehret, George B A1 - Homuth, Georg A1 - Coassin, Stefan A1 - Thun, Gian-Andri A1 - Pistis, Giorgio A1 - Gambaro, Giovanni A1 - Malerba, Giovanni A1 - Montgomery, Grant W A1 - Eiriksdottir, Gudny A1 - Jacobs, Gunnar A1 - Li, Guo A1 - Wichmann, H-Erich A1 - Campbell, Harry A1 - Schmidt, Helena A1 - Wallaschofski, Henri A1 - Völzke, Henry A1 - Brenner, Hermann A1 - Kroemer, Heyo K A1 - Kramer, Holly A1 - Lin, Honghuang A1 - Leach, I Mateo A1 - Ford, Ian A1 - Guessous, Idris A1 - Rudan, Igor A1 - Prokopenko, Inga A1 - Borecki, Ingrid A1 - Heid, Iris M A1 - Kolcic, Ivana A1 - Persico, Ivana A1 - Jukema, J Wouter A1 - Wilson, James F A1 - Felix, Janine F A1 - Divers, Jasmin A1 - Lambert, Jean-Charles A1 - Stafford, Jeanette M A1 - Gaspoz, Jean-Michel A1 - Smith, Jennifer A A1 - Faul, Jessica D A1 - Wang, Jie Jin A1 - Ding, Jingzhong A1 - Hirschhorn, Joel N A1 - Attia, John A1 - Whitfield, John B A1 - Chalmers, John A1 - Viikari, Jorma A1 - Coresh, Josef A1 - Denny, Joshua C A1 - Karjalainen, Juha A1 - Fernandes, Jyotika K A1 - Endlich, Karlhans A1 - Butterbach, Katja A1 - Keene, Keith L A1 - Lohman, Kurt A1 - Portas, Laura A1 - Launer, Lenore J A1 - Lyytikäinen, Leo-Pekka A1 - Yengo, Loic A1 - Franke, Lude A1 - Ferrucci, Luigi A1 - Rose, Lynda M A1 - Kedenko, Lyudmyla A1 - Rao, Madhumathi A1 - Struchalin, Maksim A1 - Kleber, Marcus E A1 - Cavalieri, Margherita A1 - Haun, Margot A1 - Cornelis, Marilyn C A1 - Ciullo, Marina A1 - Pirastu, Mario A1 - de Andrade, Mariza A1 - McEvoy, Mark A A1 - Woodward, Mark A1 - Adam, Martin A1 - Cocca, Massimiliano A1 - Nauck, Matthias A1 - Imboden, Medea A1 - Waldenberger, Melanie A1 - Pruijm, Menno A1 - Metzger, Marie A1 - Stumvoll, Michael A1 - Evans, Michele K A1 - Sale, Michele M A1 - Kähönen, Mika A1 - Boban, Mladen A1 - Bochud, Murielle A1 - Rheinberger, Myriam A1 - Verweij, Niek A1 - Bouatia-Naji, Nabila A1 - Martin, Nicholas G A1 - Hastie, Nick A1 - Probst-Hensch, Nicole A1 - Soranzo, Nicole A1 - Devuyst, Olivier A1 - Raitakari, Olli A1 - Gottesman, Omri A1 - Franco, Oscar H A1 - Polasek, Ozren A1 - Gasparini, Paolo A1 - Munroe, Patricia B A1 - Ridker, Paul M A1 - Mitchell, Paul A1 - Muntner, Paul A1 - Meisinger, Christa A1 - Smit, Johannes H A1 - Kovacs, Peter A1 - Wild, Philipp S A1 - Froguel, Philippe A1 - Rettig, Rainer A1 - Mägi, Reedik A1 - Biffar, Reiner A1 - Schmidt, Reinhold A1 - Middelberg, Rita P S A1 - Carroll, Robert J A1 - Penninx, Brenda W A1 - Scott, Rodney J A1 - Katz, Ronit A1 - Sedaghat, Sanaz A1 - Wild, Sarah H A1 - Kardia, Sharon L R A1 - Ulivi, Sheila A1 - Hwang, Shih-Jen A1 - Enroth, Stefan A1 - Kloiber, Stefan A1 - Trompet, Stella A1 - Stengel, Bénédicte A1 - Hancock, Stephen J A1 - Turner, Stephen T A1 - Rosas, Sylvia E A1 - Stracke, Sylvia A1 - Harris, Tamara B A1 - Zeller, Tanja A1 - Zemunik, Tatijana A1 - Lehtimäki, Terho A1 - Illig, Thomas A1 - Aspelund, Thor A1 - Nikopensius, Tiit A1 - Esko, Tõnu A1 - Tanaka, Toshiko A1 - Gyllensten, Ulf A1 - Völker, Uwe A1 - Emilsson, Valur A1 - Vitart, Veronique A1 - Aalto, Ville A1 - Gudnason, Vilmundur A1 - Chouraki, Vincent A1 - Chen, Wei-Min A1 - Igl, Wilmar A1 - März, Winfried A1 - Koenig, Wolfgang A1 - Lieb, Wolfgang A1 - Loos, Ruth J F A1 - Liu, Yongmei A1 - Snieder, Harold A1 - Pramstaller, Peter P A1 - Parsa, Afshin A1 - O'Connell, Jeffrey R A1 - Susztak, Katalin A1 - Hamet, Pavel A1 - Tremblay, Johanne A1 - de Boer, Ian H A1 - Böger, Carsten A A1 - Goessling, Wolfram A1 - Chasman, Daniel I A1 - Köttgen, Anna A1 - Kao, W H Linda A1 - Fox, Caroline S KW - Gene Expression Regulation KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Renal Insufficiency, Chronic AB -

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.

VL - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26831199?dopt=Abstract ER - TY - JOUR T1 - Modulation of genetic associations with serum urate levels by body-mass-index in humans. JF - PLoS One Y1 - 2015 A1 - Huffman, Jennifer E A1 - Albrecht, Eva A1 - Teumer, Alexander A1 - Mangino, Massimo A1 - Kapur, Karen A1 - Johnson, Toby A1 - Kutalik, Zoltán A1 - Pirastu, Nicola A1 - Pistis, Giorgio A1 - Lopez, Lorna M A1 - Haller, Toomas A1 - Salo, Perttu A1 - Goel, Anuj A1 - Li, Man A1 - Tanaka, Toshiko A1 - Dehghan, Abbas A1 - Ruggiero, Daniela A1 - Malerba, Giovanni A1 - Smith, Albert V A1 - Nolte, Ilja M A1 - Portas, Laura A1 - Phipps-Green, Amanda A1 - Boteva, Lora A1 - Navarro, Pau A1 - Johansson, Åsa A1 - Hicks, Andrew A A1 - Polasek, Ozren A1 - Esko, Tõnu A1 - Peden, John F A1 - Harris, Sarah E A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Tenesa, Albert A1 - Tin, Adrienne A1 - Mihailov, Evelin A1 - Grotevendt, Anne A1 - Gislason, Gauti K A1 - Coresh, Josef A1 - d'Adamo, Pio A1 - Ulivi, Sheila A1 - Vollenweider, Peter A1 - Waeber, Gerard A1 - Campbell, Susan A1 - Kolcic, Ivana A1 - Fisher, Krista A1 - Viigimaa, Margus A1 - Metter, Jeffrey E A1 - Masciullo, Corrado A1 - Trabetti, Elisabetta A1 - Bombieri, Cristina A1 - Sorice, Rossella A1 - Döring, Angela A1 - Reischl, Eva A1 - Strauch, Konstantin A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Waldenberger, Melanie A1 - Wichmann, H-Erich A1 - Davies, Gail A1 - Gow, Alan J A1 - Dalbeth, Nicola A1 - Stamp, Lisa A1 - Smit, Johannes H A1 - Kirin, Mirna A1 - Nagaraja, Ramaiah A1 - Nauck, Matthias A1 - Schurmann, Claudia A1 - Budde, Kathrin A1 - Farrington, Susan M A1 - Theodoratou, Evropi A1 - Jula, Antti A1 - Salomaa, Veikko A1 - Sala, Cinzia A1 - Hengstenberg, Christian A1 - Burnier, Michel A1 - Mägi, Reedik A1 - Klopp, Norman A1 - Kloiber, Stefan A1 - Schipf, Sabine A1 - Ripatti, Samuli A1 - Cabras, Stefano A1 - Soranzo, Nicole A1 - Homuth, Georg A1 - Nutile, Teresa A1 - Munroe, Patricia B A1 - Hastie, Nicholas A1 - Campbell, Harry A1 - Rudan, Igor A1 - Cabrera, Claudia A1 - Haley, Chris A1 - Franco, Oscar H A1 - Merriman, Tony R A1 - Gudnason, Vilmundur A1 - Pirastu, Mario A1 - Penninx, Brenda W A1 - Snieder, Harold A1 - Metspalu, Andres A1 - Ciullo, Marina A1 - Pramstaller, Peter P A1 - van Duijn, Cornelia M A1 - Ferrucci, Luigi A1 - Gambaro, Giovanni A1 - Deary, Ian J A1 - Dunlop, Malcolm G A1 - Wilson, James F A1 - Gasparini, Paolo A1 - Gyllensten, Ulf A1 - Spector, Tim D A1 - Wright, Alan F A1 - Hayward, Caroline A1 - Watkins, Hugh A1 - Perola, Markus A1 - Bochud, Murielle A1 - Kao, W H Linda A1 - Caulfield, Mark A1 - Toniolo, Daniela A1 - Völzke, Henry A1 - Gieger, Christian A1 - Köttgen, Anna A1 - Vitart, Veronique AB -

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

VL - 10 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25811787?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association and functional follow-up reveals new loci for kidney function. JF - PLoS Genet Y1 - 2012 A1 - Pattaro, Cristian A1 - Köttgen, Anna A1 - Teumer, Alexander A1 - Garnaas, Maija A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Taliun, Daniel A1 - Li, Man A1 - Gao, Xiaoyi A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - O'Seaghdha, Conall M A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Liu, Ching-Ti A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Johnson, Andrew D A1 - Gierman, Hinco J A1 - Feitosa, Mary A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Åsa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Chouraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Cavalieri, Margherita A1 - Rao, Madhumathi A1 - Hu, Frank B A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Kolcic, Ivana A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Endlich, Karlhans A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Ketkar, Shamika A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Giulianini, Franco A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Metzger, Marie A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Kim, Stuart K A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Siscovick, David S A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline C M A1 - Hayward, Caroline A1 - Ridker, Paul A1 - Parsa, Afshin A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Goessling, Wolfram A1 - Chasman, Daniel I A1 - Kao, W H Linda A1 - Fox, Caroline S KW - African Americans KW - Aged KW - Animals KW - Caspase 9 KW - Cyclin-Dependent Kinases KW - DEAD-box RNA Helicases KW - DNA Helicases KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Gene Knockdown Techniques KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Phosphoric Diester Hydrolases KW - Zebrafish AB -

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.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract ER - TY - JOUR T1 - Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function. JF - Hum Mol Genet Y1 - 2012 A1 - Chasman, Daniel I A1 - Fuchsberger, Christian A1 - Pattaro, Cristian A1 - Teumer, Alexander A1 - Böger, Carsten A A1 - Endlich, Karlhans A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Taliun, Daniel A1 - Li, Man A1 - Gao, Xiaoyi A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - O'Seaghdha, Conall M A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Liu, Ching-Ti A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Johnson, Andrew D A1 - Gierman, Hinco J A1 - Feitosa, Mary F A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Åsa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Lambert, Jean-Charles A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Coassin, Stefan A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Cavalieri, Margherita A1 - Rao, Madhumathi A1 - Hu, Frank A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Giulianini, Franco A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Meisinger, Christa A1 - Gieger, Christian A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Stengel, Bénédicte A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Ketkar, Shamika A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Kim, Stuart K A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Siscovick, David S A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline A1 - Hayward, Caroline A1 - Ridker, Paul M A1 - Parsa, Afshin A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Kao, W H Linda A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Amino Acid Transport Systems, Basic KW - Antigens, CD98 Heavy Chain KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Inhibin-beta Subunits KW - Intracellular Signaling Peptides and Proteins KW - Low Density Lipoprotein Receptor-Related Protein-2 KW - Membrane Proteins KW - Polymorphism, Single Nucleotide AB -

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 × 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 × 10(-4)-2.2 × 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.

VL - 21 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22962313?dopt=Abstract ER -