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

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 (nDM = 178,691, nnoDM = 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.