TY - JOUR T1 - Genetic loci associated with heart rate variability and their effects on cardiac disease risk. JF - Nat Commun Y1 - 2017 A1 - Nolte, Ilja M A1 - Munoz, M Loretto A1 - Tragante, Vinicius A1 - Amare, Azmeraw T A1 - Jansen, Rick A1 - Vaez, Ahmad A1 - von der Heyde, Benedikt A1 - Avery, Christy L A1 - Bis, Joshua C A1 - Dierckx, Bram A1 - van Dongen, Jenny A1 - Gogarten, Stephanie M A1 - Goyette, Philippe A1 - Hernesniemi, Jussi A1 - Huikari, Ville A1 - Hwang, Shih-Jen A1 - Jaju, Deepali A1 - Kerr, Kathleen F A1 - Kluttig, Alexander A1 - Krijthe, Bouwe P A1 - Kumar, Jitender A1 - van der Laan, Sander W A1 - Lyytikäinen, Leo-Pekka A1 - Maihofer, Adam X A1 - Minassian, Arpi A1 - van der Most, Peter J A1 - Müller-Nurasyid, Martina A1 - Nivard, Michel A1 - Salvi, Erika A1 - Stewart, James D A1 - Thayer, Julian F A1 - Verweij, Niek A1 - Wong, Andrew A1 - Zabaneh, Delilah A1 - Zafarmand, Mohammad H A1 - Abdellaoui, Abdel A1 - Albarwani, Sulayma A1 - Albert, Christine A1 - Alonso, Alvaro A1 - Ashar, Foram A1 - Auvinen, Juha A1 - Axelsson, Tomas A1 - Baker, Dewleen G A1 - de Bakker, Paul I W A1 - Barcella, Matteo A1 - Bayoumi, Riad A1 - Bieringa, Rob J A1 - Boomsma, Dorret A1 - Boucher, Gabrielle A1 - Britton, Annie R A1 - Christophersen, Ingrid A1 - Dietrich, Andrea A1 - Ehret, George B A1 - Ellinor, Patrick T A1 - Eskola, Markku A1 - Felix, Janine F A1 - Floras, John S A1 - Franco, Oscar H A1 - Friberg, Peter A1 - Gademan, Maaike G J A1 - Geyer, Mark A A1 - Giedraitis, Vilmantas A1 - Hartman, Catharina A A1 - Hemerich, Daiane A1 - Hofman, Albert A1 - Hottenga, Jouke-Jan A1 - Huikuri, Heikki A1 - Hutri-Kähönen, Nina A1 - Jouven, Xavier A1 - Junttila, Juhani A1 - Juonala, Markus A1 - Kiviniemi, Antti M A1 - Kors, Jan A A1 - Kumari, Meena A1 - Kuznetsova, Tatiana A1 - Laurie, Cathy C A1 - Lefrandt, Joop D A1 - Li, Yong A1 - Li, Yun A1 - Liao, Duanping A1 - Limacher, Marian C A1 - Lin, Henry J A1 - Lindgren, Cecilia M A1 - Lubitz, Steven A A1 - Mahajan, Anubha A1 - McKnight, Barbara A1 - Zu Schwabedissen, Henriette Meyer A1 - Milaneschi, Yuri A1 - Mononen, Nina A1 - Morris, Andrew P A1 - Nalls, Mike A A1 - Navis, Gerjan A1 - Neijts, Melanie A1 - Nikus, Kjell A1 - North, Kari E A1 - O'Connor, Daniel T A1 - Ormel, Johan A1 - Perz, Siegfried A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Risbrough, Victoria B A1 - Sinner, Moritz F A1 - Siscovick, David A1 - Smit, Johannes H A1 - Smith, Nicholas L A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Staessen, Jan A A1 - Stein, Phyllis K A1 - Stilp, Adrienne M A1 - Stolarz-Skrzypek, Katarzyna A1 - Strauch, Konstantin A1 - Sundström, Johan A1 - Swenne, Cees A A1 - Syvänen, Ann-Christine A1 - Tardif, Jean-Claude A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thornton, Timothy A A1 - Tinker, Lesley E A1 - Uitterlinden, André G A1 - van Setten, Jessica A1 - Voss, Andreas A1 - Waldenberger, Melanie A1 - Wilhelmsen, Kirk C A1 - Willemsen, Gonneke A1 - Wong, Quenna A1 - Zhang, Zhu-Ming A1 - Zonderman, Alan B A1 - Cusi, Daniele A1 - Evans, Michele K A1 - Greiser, Halina K A1 - van der Harst, Pim A1 - Hassan, Mohammad A1 - Ingelsson, Erik A1 - Jarvelin, Marjo-Riitta A1 - Kääb, Stefan A1 - Kähönen, Mika A1 - Kivimaki, Mika A1 - Kooperberg, Charles A1 - Kuh, Diana A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Nievergelt, Caroline M A1 - O'Donnell, Chris J A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda A1 - Reiner, Alexander P A1 - Riese, Harriëtte A1 - van Roon, Arie M A1 - Rioux, John D A1 - Rotter, Jerome I A1 - Sofer, Tamar A1 - Stricker, Bruno H A1 - Tiemeier, Henning A1 - Vrijkotte, Tanja G M A1 - Asselbergs, Folkert W A1 - Brundel, Bianca J J M A1 - Heckbert, Susan R A1 - Whitsel, Eric A A1 - den Hoed, Marcel A1 - Snieder, Harold A1 - de Geus, Eco J C AB -

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 VL - 8 ER - TY - JOUR T1 - A catalog of genetic loci associated with kidney function from analyses of a million individuals. JF - Nat Genet Y1 - 2019 A1 - Wuttke, Matthias A1 - Li, Yong A1 - Li, Man A1 - Sieber, Karsten B A1 - Feitosa, Mary F A1 - Gorski, Mathias A1 - Tin, Adrienne A1 - Wang, Lihua A1 - Chu, Audrey Y A1 - Hoppmann, Anselm A1 - Kirsten, Holger A1 - Giri, Ayush A1 - Chai, Jin-Fang A1 - Sveinbjornsson, Gardar A1 - Tayo, Bamidele O A1 - Nutile, Teresa A1 - Fuchsberger, Christian A1 - Marten, Jonathan A1 - Cocca, Massimiliano A1 - Ghasemi, Sahar A1 - Xu, Yizhe A1 - Horn, Katrin A1 - Noce, Damia A1 - van der Most, Peter J A1 - Sedaghat, Sanaz A1 - Yu, Zhi A1 - Akiyama, Masato A1 - Afaq, Saima A1 - Ahluwalia, Tarunveer S A1 - Almgren, Peter A1 - Amin, Najaf A1 - Arnlöv, Johan A1 - Bakker, Stephan J L A1 - Bansal, Nisha A1 - Baptista, Daniela A1 - Bergmann, Sven A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Boissel, Mathilde A1 - Bottinger, Erwin P A1 - Boutin, Thibaud S A1 - Brenner, Hermann A1 - Brumat, Marco A1 - Burkhardt, Ralph A1 - Butterworth, Adam S A1 - Campana, Eric A1 - Campbell, Archie A1 - Campbell, Harry A1 - Canouil, Mickaël A1 - Carroll, Robert J A1 - Catamo, Eulalia A1 - Chambers, John C A1 - Chee, Miao-Ling A1 - Chee, Miao-Li A1 - Chen, Xu A1 - Cheng, Ching-Yu A1 - Cheng, Yurong A1 - Christensen, Kaare A1 - Cifkova, Renata A1 - Ciullo, Marina A1 - Concas, Maria Pina A1 - Cook, James P A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Sala, Cinzia Felicita A1 - Cusi, Daniele A1 - Danesh, John A1 - Daw, E Warwick A1 - de Borst, Martin H A1 - De Grandi, Alessandro A1 - de Mutsert, Renée A1 - de Vries, Aiko P J A1 - Degenhardt, Frauke A1 - Delgado, Graciela A1 - Demirkan, Ayse A1 - Di Angelantonio, Emanuele A1 - Dittrich, Katalin A1 - Divers, Jasmin A1 - Dorajoo, Rajkumar A1 - Eckardt, Kai-Uwe A1 - Ehret, Georg A1 - Elliott, Paul A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Felix, Janine F A1 - Foo, Valencia Hui Xian A1 - Franco, Oscar H A1 - Franke, Andre A1 - Freedman, Barry I A1 - Freitag-Wolf, Sandra A1 - Friedlander, Yechiel A1 - Froguel, Philippe A1 - Gansevoort, Ron T A1 - Gao, He A1 - Gasparini, Paolo A1 - Gaziano, J Michael A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Giulianini, Franco A1 - Gögele, Martin A1 - Gordon, Scott D A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Haller, Toomas A1 - Hamet, Pavel A1 - Harris, Tamara B A1 - Hartman, Catharina A A1 - Hayward, Caroline A1 - Hellwege, Jacklyn N A1 - Heng, Chew-Kiat A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Huang, Wei A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Indridason, Olafur S A1 - Ingelsson, Erik A1 - Ising, Marcus A1 - Jaddoe, Vincent W V A1 - Jakobsdottir, Johanna A1 - Jonas, Jost B A1 - Joshi, Peter K A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kammerer, Candace M A1 - Kanai, Masahiro A1 - Kastarinen, Mika A1 - Kerr, Shona M A1 - Khor, Chiea-Chuen A1 - Kiess, Wieland A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kovacs, Peter A1 - Kraja, Aldi T A1 - Krajcoviechova, Alena A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Kuhnel, Brigitte A1 - Kuokkanen, Mikko A1 - Kuusisto, Johanna A1 - La Bianca, Martina A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Lee, Jeannette Jen-Mai A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Lieb, Wolfgang A1 - Lim, Su-Chi A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Liu, Jun A1 - Liu, Jianjun A1 - Loeffler, Markus A1 - Loos, Ruth J F A1 - Lucae, Susanne A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Magnusson, Patrik K E A1 - Mahajan, Anubha A1 - Martin, Nicholas G A1 - Martins, Jade A1 - März, Winfried A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mikaelsdottir, Evgenia K A1 - Milaneschi, Yuri A1 - Miliku, Kozeta A1 - Mishra, Pashupati P A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - O'Connell, Jeffrey A1 - O'Donoghue, Michelle L A1 - Olafsson, Isleifur A1 - Oldehinkel, Albertine J A1 - Orho-Melander, Marju A1 - Ouwehand, Willem H A1 - Padmanabhan, Sandosh A1 - Palmer, Nicholette D A1 - Palsson, Runolfur A1 - Penninx, Brenda W J H A1 - Perls, Thomas A1 - Perola, Markus A1 - Pirastu, Mario A1 - Pirastu, Nicola A1 - Pistis, Giorgio A1 - Podgornaia, Anna I A1 - Polasek, Ozren A1 - Ponte, Belen A1 - Porteous, David J A1 - Poulain, Tanja A1 - Pramstaller, Peter P A1 - Preuss, Michael H A1 - Prins, Bram P A1 - Province, Michael A A1 - Rabelink, Ton J A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Reilly, Dermot F A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rizzi, Federica A1 - Roberts, David J A1 - Robino, Antonietta A1 - Rossing, Peter A1 - Rudan, Igor A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Saba, Yasaman A1 - Sabanayagam, Charumathi A1 - Salomaa, Veikko A1 - Salvi, Erika A1 - Saum, Kai-Uwe A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Schupf, Nicole A1 - Shaffer, Christian M A1 - Shi, Yuan A1 - Smith, Albert V A1 - Smith, Blair H A1 - Soranzo, Nicole A1 - Spracklen, Cassandra N A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Stumvoll, Michael A1 - Svensson, Per O A1 - Szymczak, Silke A1 - Tai, E-Shyong A1 - Tajuddin, Salman M A1 - Tan, Nicholas Y Q A1 - Taylor, Kent D A1 - Teren, Andrej A1 - Tham, Yih-Chung A1 - Thiery, Joachim A1 - Thio, Chris H L A1 - Thomsen, Hauke A1 - Thorleifsson, Gudmar A1 - Toniolo, Daniela A1 - Tönjes, Anke A1 - Tremblay, Johanne A1 - Tzoulaki, Ioanna A1 - Uitterlinden, André G A1 - Vaccargiu, Simona A1 - van Dam, Rob M A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Velez Edward, Digna R A1 - Verweij, Niek A1 - Vogelezang, Suzanne A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Wang, Ya Xing A1 - Wang, Chaolong A1 - Waterworth, Dawn M A1 - Bin Wei, Wen A1 - White, Harvey A1 - Whitfield, John B A1 - Wild, Sarah H A1 - Wilson, James F A1 - Wojczynski, Mary K A1 - Wong, Charlene A1 - Wong, Tien-Yin A1 - Xu, Liang A1 - Yang, Qiong A1 - Yasuda, Masayuki A1 - Yerges-Armstrong, Laura M A1 - Zhang, Weihua A1 - Zonderman, Alan B A1 - Rotter, Jerome I A1 - Bochud, Murielle A1 - Psaty, Bruce M A1 - Vitart, Veronique A1 - Wilson, James G A1 - Dehghan, Abbas A1 - Parsa, Afshin A1 - Chasman, Daniel I A1 - Ho, Kevin A1 - Morris, Andrew P A1 - Devuyst, Olivier A1 - Akilesh, Shreeram A1 - Pendergrass, Sarah A A1 - Sim, Xueling A1 - Böger, Carsten A A1 - Okada, Yukinori A1 - Edwards, Todd L A1 - Snieder, Harold A1 - Stefansson, Kari A1 - Hung, Adriana M A1 - Heid, Iris M A1 - Scholz, Markus A1 - Teumer, Alexander A1 - Köttgen, Anna A1 - Pattaro, Cristian KW - Chromosome Mapping KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Inheritance Patterns KW - Kidney Function Tests KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Renal Insufficiency, Chronic KW - Uromodulin AB -

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

VL - 51 IS - 6 ER - TY - JOUR T1 - Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. JF - Nat Genet Y1 - 2019 A1 - Tin, Adrienne A1 - Marten, Jonathan A1 - Halperin Kuhns, Victoria L A1 - Li, Yong A1 - Wuttke, Matthias A1 - Kirsten, Holger A1 - Sieber, Karsten B A1 - Qiu, Chengxiang A1 - Gorski, Mathias A1 - Yu, Zhi A1 - Giri, Ayush A1 - Sveinbjornsson, Gardar A1 - Li, Man A1 - Chu, Audrey Y A1 - Hoppmann, Anselm A1 - O'Connor, Luke J A1 - Prins, Bram A1 - Nutile, Teresa A1 - Noce, Damia A1 - Akiyama, Masato A1 - Cocca, Massimiliano A1 - Ghasemi, Sahar A1 - van der Most, Peter J A1 - Horn, Katrin A1 - Xu, Yizhe A1 - Fuchsberger, Christian A1 - Sedaghat, Sanaz A1 - Afaq, Saima A1 - Amin, Najaf A1 - Arnlöv, Johan A1 - Bakker, Stephan J L A1 - Bansal, Nisha A1 - Baptista, Daniela A1 - Bergmann, Sven A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Boutin, Thibaud S A1 - Brumat, Marco A1 - Burkhardt, Ralph A1 - Campana, Eric A1 - Campbell, Archie A1 - Campbell, Harry A1 - Carroll, Robert J A1 - Catamo, Eulalia A1 - Chambers, John C A1 - Ciullo, Marina A1 - Concas, Maria Pina A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Cusi, Daniele A1 - Felicita, Sala Cinzia A1 - de Borst, Martin H A1 - De Grandi, Alessandro A1 - de Mutsert, Renée A1 - de Vries, Aiko P J A1 - Delgado, Graciela A1 - Demirkan, Ayse A1 - Devuyst, Olivier A1 - Dittrich, Katalin A1 - Eckardt, Kai-Uwe A1 - Ehret, Georg A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Gansevoort, Ron T A1 - Gasparini, Paolo A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Gögele, Martin A1 - Gordon, Scott D A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Haller, Toomas A1 - Hamet, Pavel A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Holm, Hilma A1 - Huang, Wei A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Lewis, Raychel M A1 - Ingelsson, Erik A1 - Jakobsdottir, Johanna A1 - Jonsdottir, Ingileif A1 - Jonsson, Helgi A1 - Joshi, Peter K A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Kerr, Shona M A1 - Kiess, Wieland A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kovacs, Peter A1 - Krämer, Bernhard K A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Kuhnel, Brigitte A1 - La Bianca, Martina A1 - Lange, Leslie A A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Liu, Jun A1 - Loeffler, Markus A1 - Loos, Ruth J F A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Martin, Nicholas G A1 - März, Winfried A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - O'Donnell, Christopher J A1 - Wilson, Otis D A1 - Gaziano, J Michael A1 - Mishra, Pashupati P A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Müller-Nurasyid, Martina A1 - Nadkarni, Girish N A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - O'Connell, Jeffrey R A1 - Olafsson, Isleifur A1 - Padmanabhan, Sandosh A1 - Penninx, Brenda W J H A1 - Perls, Thomas A1 - Peters, Annette A1 - Pirastu, Mario A1 - Pirastu, Nicola A1 - Pistis, Giorgio A1 - Polasek, Ozren A1 - Ponte, Belen A1 - Porteous, David J A1 - Poulain, Tanja A1 - Preuss, Michael H A1 - Rabelink, Ton J A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Rizzi, Federica A1 - Robino, Antonietta A1 - Rudan, Igor A1 - Krajcoviechova, Alena A1 - Cifkova, Renata A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Saba, Yasaman A1 - Salvi, Erika A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Shaffer, Christian M A1 - Smith, Albert V A1 - Smith, Blair H A1 - Spracklen, Cassandra N A1 - Strauch, Konstantin A1 - Stumvoll, Michael A1 - Sulem, Patrick A1 - Tajuddin, Salman M A1 - Teren, Andrej A1 - Thiery, Joachim A1 - Thio, Chris H L A1 - Thorsteinsdottir, Unnur A1 - Toniolo, Daniela A1 - Tönjes, Anke A1 - Tremblay, Johanne A1 - Uitterlinden, André G A1 - Vaccargiu, Simona A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Verweij, Niek A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Waldenberger, Melanie A1 - Whitfield, John B A1 - Wild, Sarah H A1 - Wilson, James F A1 - Yang, Qiong A1 - Zhang, Weihua A1 - Zonderman, Alan B A1 - Bochud, Murielle A1 - Wilson, James G A1 - Pendergrass, Sarah A A1 - Ho, Kevin A1 - Parsa, Afshin A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Böger, Carsten A A1 - Snieder, Harold A1 - Butterworth, Adam S A1 - Okada, Yukinori A1 - Edwards, Todd L A1 - Stefansson, Kari A1 - Susztak, Katalin A1 - Scholz, Markus A1 - Heid, Iris M A1 - Hung, Adriana M A1 - Teumer, Alexander A1 - Pattaro, Cristian A1 - Woodward, Owen M A1 - Vitart, Veronique A1 - Köttgen, Anna AB -

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

VL - 51 IS - 10 ER - TY - JOUR T1 - Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline. JF - Kidney Int Y1 - 2020 A1 - Gorski, Mathias A1 - Jung, Bettina A1 - Li, Yong A1 - Matias-Garcia, Pamela R A1 - Wuttke, Matthias A1 - Coassin, Stefan A1 - Thio, Chris H L A1 - Kleber, Marcus E A1 - Winkler, Thomas W A1 - Wanner, Veronika A1 - Chai, Jin-Fang A1 - Chu, Audrey Y A1 - Cocca, Massimiliano A1 - Feitosa, Mary F A1 - Ghasemi, Sahar A1 - Hoppmann, Anselm A1 - Horn, Katrin A1 - Li, Man A1 - Nutile, Teresa A1 - Scholz, Markus A1 - Sieber, Karsten B A1 - Teumer, Alexander A1 - Tin, Adrienne A1 - Wang, Judy A1 - Tayo, Bamidele O A1 - Ahluwalia, Tarunveer S A1 - Almgren, Peter A1 - Bakker, Stephan J L A1 - Banas, Bernhard A1 - Bansal, Nisha A1 - Biggs, Mary L A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Brenner, Hermann A1 - Carroll, Robert J A1 - Chalmers, John A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Cheng, Ching-Yu A1 - Coresh, Josef A1 - de Borst, Martin H A1 - Degenhardt, Frauke A1 - Eckardt, Kai-Uwe A1 - Endlich, Karlhans A1 - Franke, Andre A1 - Freitag-Wolf, Sandra A1 - Gampawar, Piyush A1 - Gansevoort, Ron T A1 - Ghanbari, Mohsen A1 - Gieger, Christian A1 - Hamet, Pavel A1 - Ho, Kevin A1 - Hofer, Edith A1 - Holleczek, Bernd A1 - Xian Foo, Valencia Hui A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Josyula, Navya Shilpa A1 - Kähönen, Mika A1 - Khor, Chiea-Chuen A1 - Koenig, Wolfgang A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kuhnel, Brigitte A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Lieb, Wolfgang A1 - Loos, Ruth J F A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Milaneschi, Yuri A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - O'Donoghue, Michelle L A1 - Orho-Melander, Marju A1 - Pendergrass, Sarah A A1 - Penninx, Brenda W J H A1 - Preuss, Michael H A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Rosenkranz, Alexander R A1 - Rossing, Peter A1 - Rotter, Jerome I A1 - Sabanayagam, Charumathi A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Sedaghat, Sanaz A1 - Shaffer, Christian M A1 - Strauch, Konstantin A1 - Szymczak, Silke A1 - Taylor, Kent D A1 - Tremblay, Johanne A1 - Chaker, Layal A1 - van der Harst, Pim A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Völker, Uwe A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Waterworth, Dawn M A1 - White, Harvey D A1 - Wilson, James G A1 - Wong, Tien-Yin A1 - Woodward, Mark A1 - Yang, Qiong A1 - Yasuda, Masayuki A1 - Yerges-Armstrong, Laura M A1 - Zhang, Yan A1 - Snieder, Harold A1 - Wanner, Christoph A1 - Böger, Carsten A A1 - Köttgen, Anna A1 - Kronenberg, Florian A1 - Pattaro, Cristian A1 - Heid, Iris M AB -

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

ER - TY - JOUR T1 - Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. JF - Nat Commun Y1 - 2020 A1 - Ntalla, Ioanna A1 - Weng, Lu-Chen A1 - Cartwright, James H A1 - Hall, Amelia Weber A1 - Sveinbjornsson, Gardar A1 - Tucker, Nathan R A1 - Choi, Seung Hoan A1 - Chaffin, Mark D A1 - Roselli, Carolina A1 - Barnes, Michael R A1 - Mifsud, Borbala A1 - Warren, Helen R A1 - Hayward, Caroline A1 - Marten, Jonathan A1 - Cranley, James J A1 - Concas, Maria Pina A1 - Gasparini, Paolo A1 - Boutin, Thibaud A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Rudan, Igor A1 - Araujo, Nathalia M A1 - Lima-Costa, Maria Fernanda A1 - Ribeiro, Antonio Luiz P A1 - Souza, Renan P A1 - Tarazona-Santos, Eduardo A1 - Giedraitis, Vilmantas A1 - Ingelsson, Erik A1 - Mahajan, Anubha A1 - Morris, Andrew P A1 - del Greco M, Fabiola A1 - Foco, Luisa A1 - Gögele, Martin A1 - Hicks, Andrew A A1 - Cook, James P A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Sundström, Johan A1 - Nelson, Christopher P A1 - Riaz, Muhammad B A1 - Samani, Nilesh J A1 - Sinagra, Gianfranco A1 - Ulivi, Sheila A1 - Kähönen, Mika A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Nikus, Kjell A1 - Caulfield, Mark J A1 - Dominiczak, Anna A1 - Padmanabhan, Sandosh A1 - Montasser, May E A1 - O'Connell, Jeff R A1 - Ryan, Kathleen A1 - Shuldiner, Alan R A1 - Aeschbacher, Stefanie A1 - Conen, David A1 - Risch, Lorenz A1 - Thériault, Sébastien A1 - Hutri-Kähönen, Nina A1 - Lehtimäki, Terho A1 - Lyytikäinen, Leo-Pekka A1 - Raitakari, Olli T A1 - Barnes, Catriona L K A1 - Campbell, Harry A1 - Joshi, Peter K A1 - Wilson, James F A1 - Isaacs, Aaron A1 - Kors, Jan A A1 - van Duijn, Cornelia M A1 - Huang, Paul L A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Smith, Albert V A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Nadkarni, Girish N A1 - Preuss, Michael H A1 - Correa, Adolfo A1 - Mei, Hao A1 - Wilson, James A1 - Meitinger, Thomas A1 - Müller-Nurasyid, Martina A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Mangino, Massimo A1 - Spector, Timothy D A1 - Rienstra, Michiel A1 - van de Vegte, Yordi J A1 - van der Harst, Pim A1 - Verweij, Niek A1 - Kääb, Stefan A1 - Schramm, Katharina A1 - Sinner, Moritz F A1 - Strauch, Konstantin A1 - Cutler, Michael J A1 - Fatkin, Diane A1 - London, Barry A1 - Olesen, Morten A1 - Roden, Dan M A1 - Benjamin Shoemaker, M A1 - Gustav Smith, J A1 - Biggs, Mary L A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Sotoodehnia, Nona A1 - De Grandi, Alessandro A1 - Fuchsberger, Christian A1 - Pattaro, Cristian A1 - Pramstaller, Peter P A1 - Ford, Ian A1 - Wouter Jukema, J A1 - Macfarlane, Peter W A1 - Trompet, Stella A1 - Dörr, Marcus A1 - Felix, Stephan B A1 - Völker, Uwe A1 - Weiss, Stefan A1 - Havulinna, Aki S A1 - Jula, Antti A1 - Sääksjärvi, Katri A1 - Salomaa, Veikko A1 - Guo, Xiuqing A1 - Heckbert, Susan R A1 - Lin, Henry J A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Yao, Jie A1 - de Mutsert, Renée A1 - Maan, Arie C A1 - Mook-Kanamori, Dennis O A1 - Noordam, Raymond A1 - Cucca, Francesco A1 - Ding, Jun A1 - Lakatta, Edward G A1 - Qian, Yong A1 - Tarasov, Kirill V A1 - Levy, Daniel A1 - Lin, Honghuang A1 - Newton-Cheh, Christopher H A1 - Lunetta, Kathryn L A1 - Murray, Alison D A1 - Porteous, David J A1 - Smith, Blair H A1 - Stricker, Bruno H A1 - Uitterlinden, Andre A1 - van den Berg, Marten E A1 - Haessler, Jeffrey A1 - Jackson, Rebecca D A1 - Kooperberg, Charles A1 - Peters, Ulrike A1 - Reiner, Alexander P A1 - Whitsel, Eric A A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Ehret, Georg B A1 - Soliman, Elsayed Z A1 - Avery, Christy L A1 - Gogarten, Stephanie M A1 - Kerr, Kathleen F A1 - Laurie, Cathy C A1 - Seyerle, Amanda A A1 - Stilp, Adrienne A1 - Assa, Solmaz A1 - Abdullah Said, M A1 - Yldau van der Ende, M A1 - Lambiase, Pier D A1 - Orini, Michele A1 - Ramirez, Julia A1 - Van Duijvenboden, Stefan A1 - Arnar, David O A1 - Gudbjartsson, Daniel F A1 - Holm, Hilma A1 - Sulem, Patrick A1 - Thorleifsson, Gudmar A1 - Thorolfsdottir, Rosa B A1 - Thorsteinsdottir, Unnur A1 - Benjamin, Emelia J A1 - Tinker, Andrew A1 - Stefansson, Kari A1 - Ellinor, Patrick T A1 - Jamshidi, Yalda A1 - Lubitz, Steven A A1 - Munroe, Patricia B AB -

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

VL - 11 IS - 1 ER - TY - JOUR T1 - Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. JF - Commun Biol Y1 - 2022 A1 - Winkler, Thomas W A1 - Rasheed, Humaira A1 - Teumer, Alexander A1 - Gorski, Mathias A1 - Rowan, Bryce X A1 - Stanzick, Kira J A1 - Thomas, Laurent F A1 - Tin, Adrienne A1 - Hoppmann, Anselm A1 - Chu, Audrey Y A1 - Tayo, Bamidele A1 - Thio, Chris H L A1 - Cusi, Daniele A1 - Chai, Jin-Fang A1 - Sieber, Karsten B A1 - Horn, Katrin A1 - Li, Man A1 - Scholz, Markus A1 - Cocca, Massimiliano A1 - Wuttke, Matthias A1 - van der Most, Peter J A1 - Yang, Qiong A1 - Ghasemi, Sahar A1 - Nutile, Teresa A1 - Li, Yong A1 - Pontali, Giulia A1 - Günther, Felix A1 - Dehghan, Abbas A1 - Correa, Adolfo A1 - Parsa, Afshin A1 - Feresin, Agnese A1 - de Vries, Aiko P J A1 - Zonderman, Alan B A1 - Smith, Albert V A1 - Oldehinkel, Albertine J A1 - De Grandi, Alessandro A1 - Rosenkranz, Alexander R A1 - Franke, Andre A1 - Teren, Andrej A1 - Metspalu, Andres A1 - Hicks, Andrew A A1 - Morris, Andrew P A1 - Tönjes, Anke A1 - Morgan, Anna A1 - Podgornaia, Anna I A1 - Peters, Annette A1 - Körner, Antje A1 - Mahajan, Anubha A1 - Campbell, Archie A1 - Freedman, Barry I A1 - Spedicati, Beatrice A1 - Ponte, Belen A1 - Schöttker, Ben A1 - Brumpton, Ben A1 - Banas, Bernhard A1 - Krämer, Bernhard K A1 - Jung, Bettina A1 - Åsvold, Bjørn Olav A1 - Smith, Blair H A1 - Ning, Boting A1 - Penninx, Brenda W J H A1 - Vanderwerff, Brett R A1 - Psaty, Bruce M A1 - Kammerer, Candace M A1 - Langefeld, Carl D A1 - Hayward, Caroline A1 - Spracklen, Cassandra N A1 - Robinson-Cohen, Cassianne A1 - Hartman, Catharina A A1 - Lindgren, Cecilia M A1 - Wang, Chaolong A1 - Sabanayagam, Charumathi A1 - Heng, Chew-Kiat A1 - Lanzani, Chiara A1 - Khor, Chiea-Chuen A1 - Cheng, Ching-Yu A1 - Fuchsberger, Christian A1 - Gieger, Christian A1 - Shaffer, Christian M A1 - Schulz, Christina-Alexandra A1 - Willer, Cristen J A1 - Chasman, Daniel I A1 - Gudbjartsson, Daniel F A1 - Ruggiero, Daniela A1 - Toniolo, Daniela A1 - Czamara, Darina A1 - Porteous, David J A1 - Waterworth, Dawn M A1 - Mascalzoni, Deborah A1 - Mook-Kanamori, Dennis O A1 - Reilly, Dermot F A1 - Daw, E Warwick A1 - Hofer, Edith A1 - Boerwinkle, Eric A1 - Salvi, Erika A1 - Bottinger, Erwin P A1 - Tai, E-Shyong A1 - Catamo, Eulalia A1 - Rizzi, Federica A1 - Guo, Feng A1 - Rivadeneira, Fernando A1 - Guilianini, Franco A1 - Sveinbjornsson, Gardar A1 - Ehret, Georg A1 - Waeber, Gérard A1 - Biino, Ginevra A1 - Girotto, Giorgia A1 - Pistis, Giorgio A1 - Nadkarni, Girish N A1 - Delgado, Graciela E A1 - Montgomery, Grant W A1 - Snieder, Harold A1 - Campbell, Harry A1 - White, Harvey D A1 - Gao, He A1 - Stringham, Heather M A1 - Schmidt, Helena A1 - Li, Hengtong A1 - Brenner, Hermann A1 - Holm, Hilma A1 - Kirsten, Holgen A1 - Kramer, Holly A1 - Rudan, Igor A1 - Nolte, Ilja M A1 - Tzoulaki, Ioanna A1 - Olafsson, Isleifur A1 - Martins, Jade A1 - Cook, James P A1 - Wilson, James F A1 - Halbritter, Jan A1 - Felix, Janine F A1 - Divers, Jasmin A1 - Kooner, Jaspal S A1 - Lee, Jeannette Jen-Mai A1 - O'Connell, Jeffrey A1 - Rotter, Jerome I A1 - Liu, Jianjun A1 - Xu, Jie A1 - Thiery, Joachim A1 - Arnlöv, Johan A1 - Kuusisto, Johanna A1 - Jakobsdottir, Johanna A1 - Tremblay, Johanne A1 - Chambers, John C A1 - Whitfield, John B A1 - Gaziano, John M A1 - Marten, Jonathan A1 - Coresh, Josef A1 - Jonas, Jost B A1 - Mychaleckyj, Josyf C A1 - Christensen, Kaare A1 - Eckardt, Kai-Uwe A1 - Mohlke, Karen L A1 - Endlich, Karlhans A1 - Dittrich, Katalin A1 - Ryan, Kathleen A A1 - Rice, Kenneth M A1 - Taylor, Kent D A1 - Ho, Kevin A1 - Nikus, Kjell A1 - Matsuda, Koichi A1 - Strauch, Konstantin A1 - Miliku, Kozeta A1 - Hveem, Kristian A1 - Lind, Lars A1 - Wallentin, Lars A1 - Yerges-Armstrong, Laura M A1 - Raffield, Laura M A1 - Phillips, Lawrence S A1 - Launer, Lenore J A1 - Lyytikäinen, Leo-Pekka A1 - Lange, Leslie A A1 - Citterio, Lorena A1 - Klaric, Lucija A1 - Ikram, M Arfan A1 - Ising, Marcus A1 - Kleber, Marcus E A1 - Francescatto, Margherita A1 - Concas, Maria Pina A1 - Ciullo, Marina A1 - Piratsu, Mario A1 - Orho-Melander, Marju A1 - Laakso, Markku A1 - Loeffler, Markus A1 - Perola, Markus A1 - de Borst, Martin H A1 - Gögele, Martin A1 - Bianca, Martina La A1 - Lukas, Mary Ann A1 - Feitosa, Mary F A1 - Biggs, Mary L A1 - Wojczynski, Mary K A1 - Kavousi, Maryam A1 - Kanai, Masahiro A1 - Akiyama, Masato A1 - Yasuda, Masayuki A1 - Nauck, Matthias A1 - Waldenberger, Melanie A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Boehnke, Michael A1 - Preuss, Michael H A1 - Stumvoll, Michael A1 - Province, Michael A A1 - Evans, Michele K A1 - O'Donoghue, Michelle L A1 - Kubo, Michiaki A1 - Kähönen, Mika A1 - Kastarinen, Mika A1 - Nalls, Mike A A1 - Kuokkanen, Mikko A1 - Ghanbari, Mohsen A1 - Bochud, Murielle A1 - Josyula, Navya Shilpa A1 - Martin, Nicholas G A1 - Tan, Nicholas Y Q A1 - Palmer, Nicholette D A1 - Pirastu, Nicola A1 - Schupf, Nicole A1 - Verweij, Niek A1 - Hutri-Kähönen, Nina A1 - Mononen, Nina A1 - Bansal, Nisha A1 - Devuyst, Olivier A1 - Melander, Olle A1 - Raitakari, Olli T A1 - Polasek, Ozren A1 - Manunta, Paolo A1 - Gasparini, Paolo A1 - Mishra, Pashupati P A1 - Sulem, Patrick A1 - Magnusson, Patrik K E A1 - Elliott, Paul A1 - Ridker, Paul M A1 - Hamet, Pavel A1 - Svensson, Per O A1 - Joshi, Peter K A1 - Kovacs, Peter A1 - Pramstaller, Peter P A1 - Rossing, Peter A1 - Vollenweider, Peter A1 - van der Harst, Pim A1 - Dorajoo, Rajkumar A1 - Sim, Ralene Z H A1 - Burkhardt, Ralph A1 - Tao, Ran A1 - Noordam, Raymond A1 - Mägi, Reedik A1 - Schmidt, Reinhold A1 - de Mutsert, Renée A1 - Rueedi, Rico A1 - van Dam, Rob M A1 - Carroll, Robert J A1 - Gansevoort, Ron T A1 - Loos, Ruth J F A1 - Felicita, Sala Cinzia A1 - Sedaghat, Sanaz A1 - Padmanabhan, Sandosh A1 - Freitag-Wolf, Sandra A1 - Pendergrass, Sarah A A1 - Graham, Sarah E A1 - Gordon, Scott D A1 - Hwang, Shih-Jen A1 - Kerr, Shona M A1 - Vaccargiu, Simona A1 - Patil, Snehal B A1 - Hallan, Stein A1 - Bakker, Stephan J L A1 - Lim, Su-Chi A1 - Lucae, Susanne A1 - Vogelezang, Suzanne A1 - Bergmann, Sven A1 - Corre, Tanguy A1 - Ahluwalia, Tarunveer S A1 - Lehtimäki, Terho A1 - Boutin, Thibaud S A1 - Meitinger, Thomas A1 - Wong, Tien-Yin A1 - Bergler, Tobias A1 - Rabelink, Ton J A1 - Esko, Tõnu A1 - Haller, Toomas A1 - Thorsteinsdottir, Unnur A1 - Völker, Uwe A1 - Foo, Valencia Hui Xian A1 - Salomaa, Veikko A1 - Vitart, Veronique A1 - Giedraitis, Vilmantas A1 - Gudnason, Vilmundur A1 - Jaddoe, Vincent W V A1 - Huang, Wei A1 - Zhang, Weihua A1 - Wei, Wen Bin A1 - Kiess, Wieland A1 - März, Winfried A1 - Koenig, Wolfgang A1 - Lieb, Wolfgang A1 - Gào, Xīn A1 - Sim, Xueling A1 - Wang, Ya Xing A1 - Friedlander, Yechiel A1 - Tham, Yih-Chung A1 - Kamatani, Yoichiro A1 - Okada, Yukinori A1 - Milaneschi, Yuri A1 - Yu, Zhi A1 - Stark, Klaus J A1 - Stefansson, Kari A1 - Böger, Carsten A A1 - Hung, Adriana M A1 - Kronenberg, Florian A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Heid, Iris M KW - Creatinine KW - Diabetes Mellitus KW - Diabetic Nephropathies KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney AB -

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

VL - 5 IS - 1 ER - TY - JOUR T1 - Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies. JF - Kidney Int Y1 - 2022 A1 - Gorski, Mathias A1 - Rasheed, Humaira A1 - Teumer, Alexander A1 - Thomas, Laurent F A1 - Graham, Sarah E A1 - Sveinbjornsson, Gardar A1 - Winkler, Thomas W A1 - Günther, Felix A1 - Stark, Klaus J A1 - Chai, Jin-Fang A1 - Tayo, Bamidele O A1 - Wuttke, Matthias A1 - Li, Yong A1 - Tin, Adrienne A1 - Ahluwalia, Tarunveer S A1 - Arnlöv, Johan A1 - Åsvold, Bjørn Olav A1 - Bakker, Stephan J L A1 - Banas, Bernhard A1 - Bansal, Nisha A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Böhnke, Michael A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Brenner, Hermann A1 - Brumpton, Ben A1 - Carroll, Robert J A1 - Chaker, Layal A1 - Chalmers, John A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Cheng, Ching-Yu A1 - Chu, Audrey Y A1 - Ciullo, Marina A1 - Cocca, Massimiliano A1 - Cook, James P A1 - Coresh, Josef A1 - Cusi, Daniele A1 - de Borst, Martin H A1 - Degenhardt, Frauke A1 - Eckardt, Kai-Uwe A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Feitosa, Mary F A1 - Franke, Andre A1 - Freitag-Wolf, Sandra A1 - Fuchsberger, Christian A1 - Gampawar, Piyush A1 - Gansevoort, Ron T A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Gudbjartsson, Daniel F A1 - Hallan, Stein A1 - Hamet, Pavel A1 - Hishida, Asahi A1 - Ho, Kevin A1 - Hofer, Edith A1 - Holleczek, Bernd A1 - Holm, Hilma A1 - Hoppmann, Anselm A1 - Horn, Katrin A1 - Hutri-Kähönen, Nina A1 - Hveem, Kristian A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Karabegović, Irma A1 - Khor, Chiea-Chuen A1 - Koenig, Wolfgang A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kuhnel, Brigitte A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Li, Man A1 - Lieb, Wolfgang A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Loos, Ruth J F A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Matias-Garcia, Pamela R A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Milaneschi, Yuri A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Morris, Andrew P A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Naito, Mariko A1 - Nakatochi, Masahiro A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Nutile, Teresa A1 - O'Donoghue, Michelle L A1 - O'Connell, Jeffrey A1 - Olafsson, Isleifur A1 - Orho-Melander, Marju A1 - Parsa, Afshin A1 - Pendergrass, Sarah A A1 - Penninx, Brenda W J H A1 - Pirastu, Mario A1 - Preuss, Michael H A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Rizzi, Federica A1 - Rosenkranz, Alexander R A1 - Rossing, Peter A1 - Rotter, Jerome I A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Sabanayagam, Charumathi A1 - Salvi, Erika A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Scholz, Markus A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Sedaghat, Sanaz A1 - Shaffer, Christian M A1 - Sieber, Karsten B A1 - Sim, Xueling A1 - Sims, Mario A1 - Snieder, Harold A1 - Stanzick, Kira J A1 - Thorsteinsdottir, Unnur A1 - Stocker, Hannah A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Sulem, Patrick A1 - Szymczak, Silke A1 - Taylor, Kent D A1 - Thio, Chris H L A1 - Tremblay, Johanne A1 - Vaccargiu, Simona A1 - van der Harst, Pim A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Völker, Uwe A1 - Wakai, Kenji A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Wallner, Stefan A1 - Wang, Judy A1 - Waterworth, Dawn M A1 - White, Harvey D A1 - Willer, Cristen J A1 - Wong, Tien-Yin A1 - Woodward, Mark A1 - Yang, Qiong A1 - Yerges-Armstrong, Laura M A1 - Zimmermann, Martina A1 - Zonderman, Alan B A1 - Bergler, Tobias A1 - Stefansson, Kari A1 - Böger, Carsten A A1 - Pattaro, Cristian A1 - Köttgen, Anna A1 - Kronenberg, Florian A1 - Heid, Iris M AB -

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

ER - TY - JOUR T1 - X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements. JF - Nat Commun Y1 - 2024 A1 - Scholz, Markus A1 - Horn, Katrin A1 - Pott, Janne A1 - Wuttke, Matthias A1 - Kühnapfel, Andreas A1 - Nasr, M Kamal A1 - Kirsten, Holger A1 - Li, Yong A1 - Hoppmann, Anselm A1 - Gorski, Mathias A1 - Ghasemi, Sahar A1 - Li, Man A1 - Tin, Adrienne A1 - Chai, Jin-Fang A1 - Cocca, Massimiliano A1 - Wang, Judy A1 - Nutile, Teresa A1 - Akiyama, Masato A1 - Åsvold, Bjørn Olav A1 - Bansal, Nisha A1 - Biggs, Mary L A1 - Boutin, Thibaud A1 - Brenner, Hermann A1 - Brumpton, Ben A1 - Burkhardt, Ralph A1 - Cai, Jianwen A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chalmers, John A1 - Chasman, Daniel I A1 - Chee, Miao Ling A1 - Chee, Miao Li A1 - Chen, Xu A1 - Cheng, Ching-Yu A1 - Cifkova, Renata A1 - Daviglus, Martha A1 - Delgado, Graciela A1 - Dittrich, Katalin A1 - Edwards, Todd L A1 - Endlich, Karlhans A1 - Michael Gaziano, J A1 - Giri, Ayush A1 - Giulianini, Franco A1 - Gordon, Scott D A1 - Gudbjartsson, Daniel F A1 - Hallan, Stein A1 - Hamet, Pavel A1 - Hartman, Catharina A A1 - Hayward, Caroline A1 - Heid, Iris M A1 - Hellwege, Jacklyn N A1 - Holleczek, Bernd A1 - Holm, Hilma A1 - Hutri-Kähönen, Nina A1 - Hveem, Kristian A1 - Isermann, Berend A1 - Jonas, Jost B A1 - Joshi, Peter K A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Kastarinen, Mika A1 - Khor, Chiea Chuen A1 - Kiess, Wieland A1 - Kleber, Marcus E A1 - Körner, Antje A1 - Kovacs, Peter A1 - Krajcoviechova, Alena A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kuokkanen, Mikko A1 - Kähönen, Mika A1 - Lange, Leslie A A1 - Lash, James P A1 - Lehtimäki, Terho A1 - Li, Hengtong A1 - Lin, Bridget M A1 - Liu, Jianjun A1 - Loeffler, Markus A1 - Lyytikäinen, Leo-Pekka A1 - Magnusson, Patrik K E A1 - Martin, Nicholas G A1 - Matsuda, Koichi A1 - Milaneschi, Yuri A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Mychaleckyj, Josyf C A1 - März, Winfried A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - Okada, Yukinori A1 - Olafsson, Isleifur A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Perola, Markus A1 - Pirastu, Nicola A1 - Polasek, Ozren A1 - Porteous, David J A1 - Poulain, Tanja A1 - Psaty, Bruce M A1 - Rabelink, Ton J A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rasheed, Humaira A1 - Reilly, Dermot F A1 - Rice, Kenneth M A1 - Richmond, Anne A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Sabanayagam, Charumathi A1 - Salomaa, Veikko A1 - Schneiderman, Neil A1 - Schöttker, Ben A1 - Sims, Mario A1 - Snieder, Harold A1 - Stark, Klaus J A1 - Stefansson, Kari A1 - Stocker, Hannah A1 - Stumvoll, Michael A1 - Sulem, Patrick A1 - Sveinbjornsson, Gardar A1 - Svensson, Per O A1 - Tai, E-Shyong A1 - Taylor, Kent D A1 - Tayo, Bamidele O A1 - Teren, Andrej A1 - Tham, Yih-Chung A1 - Thiery, Joachim A1 - Thio, Chris H L A1 - Thomas, Laurent F A1 - Tremblay, Johanne A1 - Tönjes, Anke A1 - van der Most, Peter J A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Wang, Ya Xing A1 - Wang, Chaolong A1 - Wei, Wen Bin A1 - Whitfield, John B A1 - Wild, Sarah H A1 - Wilson, James F A1 - Winkler, Thomas W A1 - Wong, Tien-Yin A1 - Woodward, Mark A1 - Sim, Xueling A1 - Chu, Audrey Y A1 - Feitosa, Mary F A1 - Thorsteinsdottir, Unnur A1 - Hung, Adriana M A1 - Teumer, Alexander A1 - Franceschini, Nora A1 - Parsa, Afshin A1 - Köttgen, Anna A1 - Schlosser, Pascal A1 - Pattaro, Cristian KW - Androgens KW - Chromosomes, Human, X KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Kidney KW - Male KW - Polymorphism, Single Nucleotide KW - Response Elements KW - Tetraspanins AB -

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

VL - 15 IS - 1 ER -