A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
Authors: van Zuydam Natalie R. , Ahlqvist Emma , Sandholm Niina , Deshmukh Harshal , Rayner N. William , Abdalla Moustafa , Ladenvall Claes , Ziemek Daniel , Fauman Eric , Robertson Neil R. , McKeigue Paul M. , Valo Erkka , Forsblom Carol , Harjutsalo Valma , Perna Annalisa , Rurali Erica , Marcovecchio M. Loredana , Igo Robert P. , Salem Rany M. , Perico Norberto , Lajer Maria , Käräjämäki Annemari , Imamura Minako , Kubo Michiaki , Takahashi Atsushi , Sim Xueling , Liu Jianjun , van Dam Rob M. , Jiang Guozhi , Tam Claudia H.T. , Luk Andrea O.Y. , Lee Heung Man , Lim Cadmon K.P. , Szeto Cheuk Chun , So Wing Yee , Chan Juliana C.N. , Ang Su Fen , Dorajoo Rajkumar , Wang Ling , Clara Tan Si Hua , McKnight Amy-Jayne , Duffy Seamus , Pezzolesi Marcus G. , Marre Michel , Gyorgy Beata , Hadjadj Samy , Hiraki Linda T. , Ahluwalia Tarunveer S. , Almgren Peter , Schulz Christina-Alexandra , Orho-Melander Marju , Linneberg Allan , Christensen Cramer , Witte Daniel R. , Grarup Niels , Brandslund Ivan , Melander Olle , Paterson Andrew D. , Tregouet David , Maxwell Alexander P. , Lim Su Chi , Ma Ronald C.W. , Tai E Shyong , Maeda Shiro , Lyssenko Valeriya , Tuomi Tiinamaija , Krolewski Andrzej S. , Rich Stephen S. , Hirschhorn Joel N. , Florez Jose C. , Dunger David , Pedersen Oluf , Hansen Torben , Rossing Peter , Remuzzi Giuseppe , Brosnan Mary Julia , Palmer Colin N.A. , Groop Per-Henrik , Colhoun Helen M. , Groop Leif C. , McCarthy Mark I. ,   Finnish Diabetic Nephropathy Study (FinnDiane), Koivula S. , Uggeldahl T. , Forslund T. , Halonen A. , Koistinen A. , Koskiaho P. , Laukkanen M. , Saltevo J. , Tiihonen M. , Forsen M. , Granlund H. , Jonsson A.-C. , Nyroos B. , Kinnunen P. , Orvola A. , Salonen T. , Vähänen A. , Paldanius Kotka R. , Riihelä M. , Ryysy L. , Laukkanen Kemi H. , Nyländen P. , Sademies A. , Anderson S. , Asplund B. , Byskata U. , Liedes P. , Kuusela M. , Virkkala T. , Nikkola A. , Ritola E. , Niska Tapiola M. , Saarinen H. , Oukko-Ruponen Samaria E. , Virtanen T. , Lyytinen Viherlaakso A. , Kari Puistola H. , Simonen T. , Kaprio Suutarila A. , Kärkkäinen J. , Rantaeskola B. , Kääriäinen Toolo P. , Haaga J. , Pietiläinen A.-L. , Klemetti S. , Nyandoto T. , Rontu E. , Satuli-Autere S. , Toivonen Korso R. , Lansimaki H. Virtanen , Ahonen R. , Ivaska-Suomela M. , Jauhiainen A. , Laine Martinlaakso M. , Pellonpää T. , Puranen R. , Airas Myyrmaki A. , Laakso J. , Rautavaara K. , Erola Rekola M. , Jatkola E. , Lönnblad Tikkurila R. , Malm A. , Mäkelä J. , Rautamo E. , Hentunen P. , Lagerstam J. , Feodoroff M. , Gordin D. , Heikkilä O. , Hietala K. , Fagerudd J. , Korolainen M. , Kyllönen L. , Kytö J. , Lindh S. , Pettersson-Fernholm K. , Rosengård-Bärlund M. , Sandelin A. , Thorn L. , Tuomikangas J. , Vesisenaho T. , Wadén J. , Sipilä V. , Kalliomäki Forssa T. , Koskelainen J. , Nikkanen R. , Savolainen N. , Sulonen H. , Valtonen E. , Norvio L. , Hämäläinen A. , Toivanen E. , Parta Jamsa A. , Pirttiniemi I. , Aranko S. , Ervasti S. , Kauppinen-Mäkelin R. , Kuusisto A. , Leppälä T. , Nikkilä K. , Pekkonen L. , Jokelainen Kajaani S. , Kananen K. , Karjalainen M. , Kemppainen P. , Mankinen A.-M. , Reponen A. , Sankari M. , Suominen P. , Lappalainen A. , Liimatainen M. , Santaholma J. , Aimolahti A. , Huovinen E. , Ilkka V. , Lehtimäki M. , Pälikkö-Kontinen E. , Vanhanen A. , Koskinen E. , Siitonen T. , Huttunen E. , Ikäheimo R. , Karhapää P. , Kekäläinen P. , Laakso M. , Lakka T. , Lampainen E. , Moilanen L. , Tanskanen S. , Niskanen L. , Tuovinen U. , Vauhkonen I. , Voutilainen E. ,   Hong Kong Diabetes Registry Theme-based Research Scheme Project Group, Ma Ronald C.W. , Chan Juliana C.N. , Huang Yu , Lan Hui-yao , Lok Si , Tomlinson Brian , Tsui Stephen K.W. , Yu Weichuan , Yip Kevin Y.L. , Chan Ting Fung , Fan Xiaodan , So Wing Yee , Szeto Cheuk Chun , Tang Nelson , Luk Andrea O. , Tian Xiaoyu , Jiang Guozhi , Tam Claudia H.T. , Lee Heung Man , Lim Cadmon K.P. , Chan Katie K.H. , Xie Fangying , Ng Alex C.W. , Cheung Grace P.Y. , Yeung Ming-wai , Mai Shi , Xie Fei , Zhang Sen , Yu Pu , Weng Meng ,   Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group, Maxwell A.P. , McKnight A.J. , Savage D.A. , Walker J. , Thomas S. , Viberti G.C. , Boulton A.J.M. , Marshall S. , Demaine A.G. , Millward B.A. , Bain S.C. ,   GENIE (GEnetics of Nephropathy an International Effort) Consortium, Sandholm Niina , Forsblom Carol , Harjutsalo Valma , Mäkinen Ville-Petteri , Ahola Aila J. , Dahlström Emma , Gordin Daniel , Heikkilä Outi , Hietala Kustaa , Kytö Janne , Lehto Markku , Lithovius Raija , Panduru Nicolae Mircea , Parkkonen Maija , Rosengård-Bärlund Milla , Saraheimo Markku , Söderlund Jenny , Soro-Paavonen Aino , Syreeni Anna , Thorn Lena M. , Tolonen Nina , Wadén Johan , Groop Per-Henrik , McKnight Amy Jayne , McKay Gareth J. , Maxwell Alexander P. , Salem Rany M. , Isakova Tamara , Palmer Cameron , Guiducci Candace , Taylor Andrew , Mirel Daniel B. , Williams Winfred W. , Hirschhorn Joel N. , Florez Jose C. , Brennan Eoin P. , Sadlier Denise M. , Martin Finian , Godson Catherine ,   Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group, Mayer Lynne , Gubitosi-Klug Rose , Bourne Patti , Schutta Mark , Lackaye Mary Ellen , Gregory Naina Sinha , Kruger Davida , Jones J. Kimberly , Bhan Arti , Golden Ellen , Aiello Lloyd , Larkin Mary , Nathan David , Ziegler Georgia , Caulder Susan , Pittman Clare , Luttrell Louis , Lopes-Virella Maria , Johnson Mary , Gunyou Kimberly , Bergenstal Richard , Vittetoe Brenda , Sivitz William , Flaherty Nancy , Bantle John , Hitt Susan , Goldstein David , Hainsworth Dean , Cimino Lori , Orchard Trevor , Wigley Christine , Dagogo-Jack Samuel , Strowig Suzanne , Raskin Philip , Barnie Annette , Zinman Bernard , Fahlstrom Robyn , Palmer Jerry , Harth Judith , Driscoll Marsha , McDonald Charlotte , Lipps Hagan Janie , May Michael , Levandoski Lucy , White Neil , Gatcomb Patricia , Tamborlane William , Adelman Daphne , Colson Susan , Molitch Mark , Lorenzi Gayle , Mudaliar Sunder , Johnsonbaugh Sherry , Miller Ryan , Canady Janene , Schade David , Bernal Maria Luisa , Malone John , Morrison Anthony , Martin Catherine , Herman William , Pop-Busui Rodica , Cowie Catherine , Leschek Ellen , Cleary Patricia , Lachin John , Zinman Bernie , Lorenzi Gayle , Braffett Barbara , Steffes Mike , Arends Valerie , Blodi Barbara , Danis Ronald , Lawrence Daniel , Wabers Hugh , Soliman Elsayed , Zhang Zhu-Ming , Campbell Charles , Hensley Susan , Keasler Lisa ,   SUrrogate markers for Micro- and Macrovascular hard endpoints for Innovative diabetes Tools (SUMMIT) Consortium, Mark Michael , Albertini Markus , Boustany Carine , Ehlgen Alexander , Gerl Martin , Huber Jochen , Schölch Corinna , Zimdahl-Gelling Heike , Groop Leif , Agardh Elisabet , Ahlqvist Emma , Ajanki Tord , Al Maghrabi Nibal , Almgren Peter , Apelqvist Jan , Bengtsson Eva , Berglund Lisa , Björckbacka Harry , Blom-Nilsson Ulrika , Borell Mattias , Burström Agneta , Cilio Corrado , Cinthio Magnus , Dreja Karl , Dunér Pontus , Engelbertsen Daniel , Fadista Joao , Gomez Maria , Goncalves Isabel , Hedblad Bo , Hultgårdh Anna , Johansson Martin E. , Kennbäck Cecilia , Kravic Jasmina , Ladenvall Claes , Lernmark Åke , Lindholm Eero , Ling Charlotte , Luthman Holger , Melander Olle , Neptin Malin , Nilsson Jan , Nilsson Peter , Nilsson Tobias , Nordin Gunilla , Orho-Melander Marju , Ottoson-Laakso Emilia , Persson Annie , Persson Margaretha , Persson Mats-Åke , Postma Jacqueline , Pranter Elisabeth , Rattik Sara , Sterner Gunnar , Tindberg Lilian , Wigren Maria , Zetterqvist Anna , Åkerlund Mikael , Ostling Gerd , Kanninen Timo , Ahonen-Bishopp Anni , Eliasson Anita , Herrala Timo , Tikka-Kleemola Paivi , Hamsten Anders , Betsholtz Christer , Björkholm Ami , Foroogh Fariba , Genové Guillem , Gertow Karl , Gigante Bruna , He Bing , Leander Karin , McLeod Olga , Nastase-Mannila Maria , Patrakka Jaako , Silveira Angela , Strawbridge Rona , Tryggvason Karl , Vikström Max , Ohrvik John , Österholm Anne-May , Thorand Barbara , Gieger Christian , Grallert Harald , Ludwig Tonia , Nitz Barbara , Schneider Andrea , Wang-Sattler Rui , Zierer Astrid , Remuzzi Giuseppe , Benigni Ariela , Donadelli Roberta , Lesti Maria Domenica , Noris Marina , Perico Norberto , Perna Annalisa , Piras Rossella , Ruggenenti Piero , Rurali Erica , Dunger David , Chassin Ludo , Dalton Neil , Deanfield John , Horsford Jane , Rice Clare , Rudd James , Walker Neil , Whitehead Karen , Wong Max , Colhoun Helen , Adams Fiona , Akbar Tahira , Belch Jill , Deshmukh Harshal , Dove Fiona , Ellingford Angela , Farran Bassam , Ferguson Mike , Henderson Gary , Houston Graeme , Khan Faisel , Leese Graham , Liu Yiyuan , Livingstone Shona , Looker Helen , McCann Margaret , McGurnaghan Stuart , Morris Andrew , Newton David , Palmer Colin , Pearson Ewan , Reekie Gillian , Smith Natalie , Shore Angela , Aizawa Kuni , Ball Claire , Bellenger Nick , Casanova Francesco , Frayling Tim , Gates Phil , Gooding Kim , Hattersley Andrew , Ling Roland , Mawson David , Shandas Robin , Strain David , Thorn Clare , Smith Ulf , Hammarstedt Ann , Häring Hans , Pedersen Oluf , Sesti Georgio , Groop Per-Henrik , Fagerholm Emma , Forsblom Carol , Harjutsalo Valma , Parkkonen Maikki , Sandholm Niina , Tolonen Nina , Toppila Iiro , Valo Erkka , Salomaa Veikko , Havulinna Aki , Kristiansson Kati , Okamo Pia , Peltola Tomi , Perola Markus , Pietilä Arto , Ripatti Samuli , Taimi Marketta , Ylä-Herttuala Seppo , Babu Mohan , Dijkstra Marike , Gurzeler Erika , Huusko Jenni , Kholová Ivana , Laakso Markku , Merentie Mari , Poikolainen Marja , McCarthy Mark , Groves Chris , Juliusdottir Thorhildur , Karpe Fredrik , Lagou Vasiliki , Morris Andrew , Rayner Will , Robertson Neil , van Zuydam Natalie , Cobelli Claudio , Di Camillo Barbara , Finotello Francesca , Sambo Francesco , Toffolo Gianna , Trifoglio Emanuele , Bellazzi Riccardo , Barbarini Nicola , Bucalo Mauro , Larizza Christiana , Magni Paolo , Malovini Alberto , Marini Simone , Mulas Francesca , Quaglini Silvana , Sacchi Lucia , Vitali Francesca , Ferrannini Ele , Boldrini Beatrice , Kozakova Michaela , Mari Andrea , Morizzo Carmela , Mota Lucrecia , Natali Andrea , Palombo Carlo , Venturi Elena , Walker Mark , Patrono Carlo , Pagliaccia Francesca , Rocca Bianca , Nuutila Pirjo , Haukkala Johanna , Knuuti Juhani , Roivainen Anne , Saraste Antti , McKeague Paul , Colombo Marco , Steckel-Hamann Birgit , Bokvist Krister , Shankar Sudha , Thomas Melissa , Gan Li-ming , Heinonen Suvi , Jönsson-Rylander Ann-Cathrine , Momo Remi , Schnecke Volker , Unwin Robert , Walentinsson Anna , Whatling Carl , Nogoceke Everson , Pacheco Gonzalo Durán , Formentini Ivan , Schindler Thomas , Tortoli Piero , Bassi Luca , Boni Enrico , Dallai Alessandro , Guidi Francesco , Lenge Matteo , Matera Riccardo , Ramalli Alessandro , Ricci Stefano , Viti Jacopo , Jablonka Bernd , Crowther Dan , Gassenhuber Johan , Hess Sibylle , Hubschle Thomas , Juretschke Hans-Paul , Rutten Hartmut , Sadowski Thorsten , Wohlfart Paulus , Brosnan Julia , Clerin Valerie , Fauman Eric , Hyde Craig , Malarstig Anders , Pullen Nick , Tilley Mera , Tuthill Theresa , Vangjeli Ciara , Ziemek Daniel 
Published: April 2018

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10−8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.