A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
Natalie R. van Zuydam(Centre for Human Genetics), Emma Ahlqvist(Lund University), Niina Sandholm(University of Helsinki), Harshal Deshmukh(Newcastle University), Nigel W. Rayner(Centre for Human Genetics), Moustafa Abdalla(Centre for Human Genetics), Claes Ladenvall(Lund University), Daniel Ziemek(Pfizer (Germany)), Eric B. Fauman(Target (United States)), Neil R. Robertson(Centre for Human Genetics), Paul McKeigue(University of Edinburgh), Erkka Valo(University of Helsinki), Carol Forsblom(University of Helsinki), Valma Harjutsalo(University of Helsinki), Annalisa Perna(Mario Negri Institute for Pharmacological Research), Erica Rurali(Mario Negri Institute for Pharmacological Research), M. Loredana Marcovecchio(University of Cambridge), Robert P. Igo(Case Western Reserve University), Rany M. Salem(University of California San Diego), Norberto Perico(Mario Negri Institute for Pharmacological Research), Maria Lajer(Steno Diabetes Centers), Annemari Käräjämäki(Vaasa Central Hospital), Minako Imamura(University of the Ryukyus), Michiaki Kubo(RIKEN Center for Integrative Medical Sciences), Atsushi Takahashi(National Cerebral and Cardiovascular Center), Xueling Sim(National University of Singapore), Jianjun Liu(Agency for Science, Technology and Research), Rob M. van Dam(National University of Singapore), Guozhi Jiang(Chinese University of Hong Kong), Claudia H.T. Tam(Chinese University of Hong Kong), Andrea O. Y. Luk(Chinese University of Hong Kong), Heung Man Lee(Chinese University of Hong Kong), Cadmon K.P. Lim(Chinese University of Hong Kong), Cheuk‐Chun Szeto(Chinese University of Hong Kong), Wing Yee So(Chinese University of Hong Kong), Juliana C.N. Chan(Chinese University of Hong Kong), Su Fen Ang(Khoo Teck Puat Hospital), Rajkumar Dorajoo(Agency for Science, Technology and Research), Ling Wang(Agency for Science, Technology and Research), Tan Si Hua Clara(Khoo Teck Puat Hospital), Amy Jayne McKnight(Queen's University Belfast), Seamus Duffy(Queen's University Belfast), Marcus G. Pezzolesi(University of Utah), Michel Marre(Inserm), Beata Gyorgy(Inserm), Samy Hadjadj(Inserm), Linda T. Hiraki(Hospital for Sick Children), Tarunveer S. Ahluwalia(University of Copenhagen), Peter Almgren(Lund University), Christina‐Alexandra Schulz(Lund University), Marju Orho‐Melander(Lund University), Allan Linneberg(University of Copenhagen), Cramer Christensen(Vejle Sygehus), Daniel R. Witte(Aarhus University), Niels Grarup(University of Copenhagen), Ivan Brandslund(University of Southern Denmark), Olle Melander(Lund University), Andrew D. Paterson(Hospital for Sick Children), David‐Alexandre Trégouët(Inserm), Alexander P. Maxwell(Queen's University Belfast), Su Chi Lim(National University of Singapore), Ronald C.W.(Chinese University of Hong Kong), E Shyong Tai(National University of Singapore), Shiro Maeda(University of the Ryukyus), Valeriya Lyssenko(Lund University), Tiinamaija Tuomi(University of Helsinki), Andrzej S. Królewski(Joslin Diabetes Center), Stephen S. Rich(University of Virginia), Joel N. Hirschhorn(Broad Institute), José C. Florez(Broad Institute), David B. Dunger(University of Cambridge), Oluf Pedersen(University of Copenhagen), Torben Hansen(University of Copenhagen), Peter Rossing(University of Copenhagen), Giuseppe Remuzzi(University of Milan), M. Julia Brosnan(Pfizer (United States)), Colin N.A. Palmer(Ninewells Hospital), Per‐Henrik Groop(University of Helsinki), Helen M. Colhoun(Institute of Genetics and Cancer), Leif Groop(University of Helsinki), Mark I. McCarthy(Centre for Human Genetics), Finnish Diabetic Nephropathy Study (FinnDiane), Satu Koivula, T. Uggeldahl, Terje Forslund, A. Halonen, A. Koistinen, P. Koskiaho, M. Laukkanen, Juha Saltevo, Miia Tiihonen, M. Forsen, Helena Granlund(Khoo Teck Puat Hospital), A.-C. Jönsson, B. Nyroos, Pentti Kinnunen, A. Orvola, Tapani Salonen, A. Vähänen, Kotka R. Paldanius, M Riihelä, L. Ryysy, Kemi H. Laukkanen, P. Nyländen, Anni Sademies, S. Anderson, Barbro Asplund, U. Byskata, P. Liedes, M. Kuusela, T. Virkkala, Anssi Nikkola, E. Ritola, Tapiola M. Niska, Harri Juhani Saarinen, Samaria E. Oukko-Ruponen, Tuula Virtanen, Viherlaakso A. Lyytinen, Puistola H. Kari, T. Simonen, Suutarila A. Kaprio, Jorma Kärkkäinen, B. Rantaeskola, Toolo P. Kääriäinen, J R Haaga, A.-L. Pietiläinen, Sanna Klemetti, T. Nyandoto, E. Rontu, Susanna Satuli-Autere, Korso R. Toivonen, H. Virtanen Lansimaki, Riitta Ahonen, M. Ivaska-Suomela, Anneli Jauhiainen, Martinlaakso M. Laine, T. Pellonpää, R. Puranen, Myyrmaki A. Airas, Juha Laakso, K. Rautavaara, Rekola M. Erola, E. Jatkola, Tikkurila R. Lönnblad, Anna Malm, Jyrki Mäkelä, E. Rautamo, P. Hentunen, J. Lagerstam, Maija Feodoroff, Daniel Gordin, Outi Heikkilä, Kustaa Hietala, J. Fagerudd, Minna A. Korolainen, L. Kyllönen, Janne Kytö, S. Lindh, K. Pettersson-Fernholm, Milla Rosengård‐Bärlund, Amanda Sandelin, Lena M. Thorn, Jaana Tuomikangas, T. Vesisenaho, Johan Wadén(University of Cambridge), V. Sipilä, Forssa T. Kalliomäki, J. Koskelainen, R. Nikkanen, N. Savolainen, Hannu Sulonen, E. Valtonen, Leena Norvio, Anne Hämäläinen, E. Toivanen, Jamsa A. Parta, I. Pirttiniemi, S. Aranko, Satu Ervasti, Ronald C.W., Ari Kuusisto, T. Leppälä, Katriina Nikkilä, L. Pekkonen, K. Jokelainen, Kristiina Kananen, Matti Karjalainen, Pentti Kemppainen(Helsinki University Hospital), A.-M. Mankinen, A. Reponen, M. Sankari, Pauli Suominen, Anu K. Lappalainen, Maarit Liimatainen, J. Santaholma, Ari Aimolahti, Elisa Huovinen(University of Cambridge), V. Ilkka, M. Y. Lehtimäki, E. Pälikkö-Kontinen, Antti Vanhanen, E. Koskinen, Timo Siitonen, Erja Huttunen, Risto Ikäheimo, Pauli Karhapää, Päivi Kekäläinen, M. Laakso, Timo A. Lakka, E Lampainen, Leena Moilanen, Sanna Tanskanen, Leo Niskanen, U. Tuovinen, Ilkka Vauhkonen, Erkki Voutilainen, Ronald C.W.(Chinese University of Hong Kong), Juliana C.N. Chan(Chinese University of Hong Kong), Yü Huang(Malmö University), Hui-yao Lan, Si Lok, Brian Tomlinson, Stephen Kwok‐Wing Tsui, Weichuan Yu, Kevin Y.L. Yip(Chinese University of Hong Kong), Ting‐Fung Chan, Xiaodan Fan, Wing Yee So(Chinese University of Hong Kong), Cheuk‐Chun Szeto(Chinese University of Hong Kong), Nelson L.S. Tang(Chinese University of Hong Kong), Andrea O. Y. Luk(Chinese University of Hong Kong), Xiaoyu Tian(Chinese University of Hong Kong), Guozhi Jiang(Chinese University of Hong Kong), Claudia H.T. Tam(Chinese University of Hong Kong), Heung Man Lee(Nanyang Technological University), Cadmon K.P. Lim(Chinese University of Hong Kong), Katie K.H. Chan, Fangying Xie, Alex C.W. Ng, Grace P.Y. Cheung, Ming Wai Yeung(Helsinki University Hospital), Shi Mai, Fei Xie, Sen Zhang, Yu Pu, Meng Weng, Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group(Queen's University Belfast), Alexander P. Maxwell(Queen's University Belfast), Amy Jayne McKnight(Queen's University Belfast), David A. Savage, James D. Walker, Stephen Thomas, Giancarlo Viberti, A.J.M. Boulton, S. M. Marshall, Andrew Demaine, B. A. Millward(University of Helsinki), Steve Baín(University of Helsinki), Niina Sandholm(University of Helsinki), Carol Forsblom(University of Helsinki), Valma Harjutsalo(University of Helsinki), Ville‐Petteri Mäkinen(Lund University), Aila J. Ahola(Aarhus University), Emma H. Dahlström, Daniel Gordin, Outi Heikkilä, Kustaa Hietala, Janne Kytö, Markku Lehto, Raija Lithovius(Helsinki University Hospital), Nicolae Mircea Panduru, Maija Parkkonen, Milla Rosengård‐Bärlund, Markku Saraheimo, Jenny Söderlund(Mario Negri Institute for Pharmacological Research), Aino Soro‐Paavonen, Anna Syreeni, Lena M. Thorn, Nina Tolonen, Johan Wadén(Queen's University Belfast), Per‐Henrik Groop(University of Helsinki), Amy Jayne McKnight(Queen's University Belfast), Gareth J. McKay(University of San Diego), Alexander P. Maxwell(Queen's University Belfast), Rany M. Salem(University of California San Diego), Tamara Isakova, Cameron Palmer(Ninewells Hospital), Candace Guiducci, Andrew M. Taylor, Daniel B. Mirel, Winfred W. Williams, Joel N. Hirschhorn(Broad Institute), José C. Florez(Broad Institute), Eoin Brennan, Denise M. Sadlier, Finian Martin, Catherine Godson, Lynne Mayer, Rose Gubitosi‐Klug, P. A. Bourne, Mark H. Schutta, M. E. Lackaye, Naina Sinha Gregory, Davida Kruger, J. Kimberly Jones, Arti Bhan, E. Golden, Lloyd Paul Aiello(University of Cambridge), Mary Larkin, David Nathan, G. Ziegler, Susan Caulder, C. Pittman(Steno Diabetes Centers), Louis M. Luttrell, Maria F. Lopes‐Virella, Mary L. Johnson, K. Gunyou, Richard M. Bergenstal(Centre for Human Genetics), B. Vittetoe, William I. Sivitz, Nancy Flaherty, John P. Bantle(University of Cambridge), Susan Hitt, David Goldstein, Dean P. Hainsworth, Lori Cimino, Trevor J. Orchard, Christine Wigley, Samuel Dagogo‐Jack, Suzanne Strowig, Philip Raskin, Annette Barnie, Bernard Zinman, Robyn Fahlstrom, Jerry P. Palmer, J. Harth, Marsha Driscoll, Charlotte McDonald, Janie Lipps Hagan, Michael May(Centre for Human Genetics), L. Levandoski, Neil H. White(Centre for Human Genetics), P. Gatcomb, William V. Tamborlane, Daphne T. Adelman, Susan Colson, Mark E. Molitch, Gayle M. Lorenzi, Sunder Mudaliar, S. Johnsonbaugh, Ryan Miller(University of Cambridge), Janene L. Canady, David S. Schade, M.L. Bernal, John I. Malone, Anthony Morrison(Centre for Human Genetics), Catherine Martin, William H. Herman, Rodica Pop‐Busui, Catherine C. Cowie, Ellen Leschek, Patricia A. Cleary, John M. Lachin, B. Zinman, Gayle M. Lorenzi, Barbara H. Braffett, Mike Steffes, Valerie Arends(Chinese University of Hong Kong), Barbara Blodi(Aarhus University), Ronald Danis, Daniel Lawrence, Hugh Wabers, Elsayed Z. Soliman, Zhu‐Ming Zhang, Charles J. Campbell(Mario Negri Institute for Pharmacological Research), Susan Hensley, Lisa Keasler, Mark Michael, Markus Albertini, Carine Boustany, Alexander Ehlgen, Martin Gerl, Jochen Huber, Corinna Schölch, Heike Zimdahl‐Gelling, Leif Groop(University of Helsinki), Elisabet Agardh, Emma Ahlqvist(Lund University), Tord Ajanki(Lund University), Nibal Al Maghrabi, Peter Almgren(Centre for Human Genetics), Jan Apelqvist(Mario Negri Institute for Pharmacological Research), Eva Bengtsson, Lisa Berglund, Harry Björckbacka, Ulrika Blom-Nilsson, Mattias Borell, Agneta Burström, Corrado Cilio, Magnus Cinthio, Karl Dreja(Aarhus University), Pontus Dunér, Daniel Engelbertsen(Steno Diabetes Centers), João Fadista, Marı́a Gómez(RIKEN Center for Integrative Medical Sciences), Isabel Gonçalves(Mario Negri Institute for Pharmacological Research), Bo Hedblad, Anna Hultgårdh, Martin E. Johansson, Cecilia Kennbäck(Lund University), Jasmina Kravić, Claes Ladenvall(Lund University), Åke Lernmark(Agency for Science, Technology and Research), Eero Lindholm, Charlotte Ling(Malmö University), Holger Luthman, Olle Melander(Lund University), Malin Neptin, Jan Nilsson, Peter M. Nilsson, Tobias Nilsson, Gunilla Nordin, Marju Orho-Melander(Lund University), Emilia Ottoson-Laakso, Annie Persson, Margaretha Persson, Mats-Åke Persson, Jacqueline Postma, Elisabeth Pranter, Sara Rattik, Gunnar Sterner(Steno Diabetes Centers), Lilian Tindberg(Mario Negri Institute for Pharmacological Research), Maria Wigren, Anna V. Zetterqvist, Mikael Åkerlund, Gerd Östling, Timo Kanninen, Anni Ahonen-Bishopp, Anita Eliasson, Timo Herrala, Päivi Tikka-Kleemola, Anders Hamsten, Christer Betsholtz, A. Björkholm, Fariba Foroogh, Guillem Genové, Karl Gertow, Bruna Gigante, Bing He, Karin Leander(Steno Diabetes Centers), Olga McLeod, Maria Nastase-Mannila, Jaako Patrakka(Chinese University of Hong Kong), Angela Silveira, Rona J. Strawbridge, Karl Tryggvason, Max Vikström, John Öhrvik, Anne‐May Österholm, Barbara Thorand, Christian Gieger, Harald Grallert, Tonia Ludwig, Barbara Nitz, Andrea L.C. Schneider, Rui Wang‐Sattler(Mario Negri Institute for Pharmacological Research), Astrid Zierer, Giuseppe Remuzzi(University of Milan), Ariela Benigni, Roberta Donadelli, Mariadomenica Lesti(Mario Negri Institute for Pharmacological Research), Marina Noris(Mario Negri Institute for Pharmacological Research), Norberto Perico(Mario Negri Institute for Pharmacological Research), Annalisa Perna(Mario Negri Institute for Pharmacological Research), Rossella Piras(Mario Negri Institute for Pharmacological Research), Piero Ruggenenti(University of Cambridge), Erica Rurali(Mario Negri Institute for Pharmacological Research), David B. Dunger(Centre for Human Genetics), Ludo Chassin, Neil Dalton, John Deanfield, Jane Horsford, Clare Rice(Centre for Human Genetics), James H.F. Rudd, Neil Walker, Karen Whitehead, Max Wong, Helen M. Colhoun(Institute of Genetics and Cancer), F. Dennette Adams, Tahira Akbar(University of Newcastle Australia), J. J. F. Belch, Harshal Deshmukh(Newcastle University), Fiona Dove, A Ellingford, Bassam Farran, Mike Ferguson, Gary L. Henderson, J. Graeme Houston, Faisel Khan(Agency for Science, Technology and Research), Graham Leese, Yiyuan Liu, Shona Livingstone, Helen C. Looker, Margaret McCann, Stuart J. McGurnaghan(University of Cambridge), Andrew D. Morris, D. J. Newton, Colin Palmer(Ninewells Hospital), Ewan R. Pearson(Centre for Human Genetics), G Reekie, Natalie Smith, Angela C. Shore, Kuni Aizawa, Claire Ball, Nick G. Bellenger, Francesco Casanova, Timothy M. Frayling, Phil Gates, Kim M. Gooding(Agency for Science, Technology and Research), Andrew T. Hattersley(University of Cambridge), R Ling, David M. Mawson(University of Cambridge), Robin Shandas, W. David Strain, Clare E. Thorn(Vaasa Central Hospital), Ulf Smith, Ann Hammarstedt, Hans Häring, Oluf Pedersen(University of Copenhagen), Georgio Sesti(Lund University), Per‐Henrik Groop(University of Helsinki), Emma Fagerholm(University of Helsinki), Carol Forsblom(University of Helsinki), Valma Harjutsalo(University of Helsinki), Maikki Parkkonen, Niina Sandholm(University of Helsinki), Nina Tolonen(University of Helsinki), Iiro Toppila, Erkka Valo(University of Helsinki), Veikko Salomaa, Aki S. Havulinna, Kati Kristiansson, Pia Okamo, Tomi Peltola, Markus Perola, Arto Pietilä, Samuli Ripatti, Marketta Taimi, Seppo Ylä‐Herttuala, Mohan Babu, Marike H. Dijkstra, Erika Gurzeler, Jenni Huusko, Ivana Kholová(Vaasa Central Hospital), Markku Laakso, Mari Merentie, Marja Poikolainen(Vejle Sygehus), Mark McCarthy(Centre for Human Genetics), Chris Groves, Thorhildur Juliusdottir, Fredrik Karpe, Vasiliki Lagou(Centre for Human Genetics), Andrew D. Morris(Centre for Human Genetics), Will Rayner(Centre for Human Genetics), Neil Robertson(Centre for Human Genetics), Natalie R. van Zuydam(Centre for Human Genetics), Claudio Cobelli, Barbara Di Camillo, Francesca Finotello, Francesco Sambo, Gianna Toffolo, Emanuele Trifoglio, Riccardo Bellazzi, Nicola Barbarini, Mauro Bucalo, Christiana Larizza, Paolo Magni, Alberto Malovini, Simone Marini, Francesca Mulas, Silvana Quaglini, Lucia Sacchi, Francesca Vitali, Ele Ferrannini, Beatrice Boldrini(Vaasa Central Hospital), M. Kozàkovà, Andrea Mari, C. Morizzo(Centre for Human Genetics), L.G.S. Mota, Andrea Natali, Carlo Palombo, Elena Venturi, Mark S. Walker, Carlo Patrono, Francesca Pagliaccia, Bianca Rocca, Pirjo Nuutila, Johanna Haukkala(Vaasa Central Hospital), Juhani Knuuti, Anne Roivainen(University of Edinburgh), Antti Saraste(University of Cambridge), Paul McKeague, Marco Colombo, Birgit Steckel-Hamann, Krister Bokvist, Sudha Shankar, Mélissa Thomas, Li‐Ming Gan, Suvi E. Heinonen, Ann‐Cathrine Jönsson‐Rylander, Remi A. Momo(Case Western Reserve University), Volker Schnecke(Mario Negri Institute for Pharmacological Research), Robert J. Unwin, Anna Walentinsson, Carl Whatling, Everson Nogoceke(University of Southern Denmark), Gonzalo Durán Pacheco, Ivan Formentini, Thomas H. Schindler, Piero Tortoli, Luca Bassi, Enrico Boni, Alessandro Dallai, Francesco Guidi, Matteo Lenge, Riccardo Matera, Alessandro Ramalli, Stefano Ricci, Jacopo Viti(Aarhus University), Bernd Jablonka, D Crowther, Johann Gassenhuber, Sibylle Hess, Thomas Hübschle, Hans‐Paul Juretschke, Hartmut Rütten, Thorsten Sadowski, Paulus Wohlfart, Julia Brosnan(Pfizer (United States)), Valérie Clerin, Eric Fauman(Target (United States)), Craig Hyde, Anders Mälarstig, Nick Pullen, Mera Tilley, Theresa Tuthill(Pfizer (United States)), Ciara Vangjeli, Daniel Ziemek(Pfizer (Germany))
Cited by 197Open Access
Abstract
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.
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