A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
Author:
van Zuydam Natalie R.12ORCID, Ahlqvist Emma3, Sandholm Niina456ORCID, Deshmukh Harshal7, Rayner N. William128, Abdalla Moustafa129, Ladenvall Claes3, Ziemek Daniel10, Fauman Eric11, Robertson Neil R.12, McKeigue Paul M.12, Valo Erkka456, Forsblom Carol456, Harjutsalo Valma45613, Perna Annalisa14, Rurali Erica14, Marcovecchio M. Loredana15, Igo Robert P.16, Salem Rany M.17, Perico Norberto14, Lajer Maria18, Käräjämäki Annemari1920, Imamura Minako212223, Kubo Michiaki23, Takahashi Atsushi2425, Sim Xueling26, Liu Jianjun262728, van Dam Rob M.26, Jiang Guozhi29, Tam Claudia H.T.29, Luk Andrea O.Y.293031, Lee Heung Man29303132, Lim Cadmon K.P.29, Szeto Cheuk Chun29, So Wing Yee29, Chan Juliana C.N.293031, Ang Su Fen33, Dorajoo Rajkumar27, Wang Ling27, Clara Tan Si Hua33, McKnight Amy-Jayne34, Duffy Seamus34, Pezzolesi Marcus G.35, Marre Michel36, Gyorgy Beata36, Hadjadj Samy373839, Hiraki Linda T.40, Ahluwalia Tarunveer S.1841, Almgren Peter42, Schulz Christina-Alexandra42, Orho-Melander Marju42, Linneberg Allan434445, Christensen Cramer46, Witte Daniel R.4748, Grarup Niels41, Brandslund Ivan4950, Melander Olle51, Paterson Andrew D.40, Tregouet David36, Maxwell Alexander P.34, Lim Su Chi525354, Ma Ronald C.W.29303132, Tai E Shyong265355, Maeda Shiro212223, Lyssenko Valeriya356, Tuomi Tiinamaija465758, Krolewski Andrzej S.59, Rich Stephen S.60, Hirschhorn Joel N.616263, Florez Jose C.626465, Dunger David1566ORCID, Pedersen Oluf41, Hansen Torben4167, Rossing Peter1841, Remuzzi Giuseppe146869, Brosnan Mary Julia70, Palmer Colin N.A.71, Groop Per-Henrik45672ORCID, Colhoun Helen M.73ORCID, Groop Leif C.358, McCarthy Mark I.1274, 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., 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, 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., 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, 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, 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, , , , , ,
Affiliation:
1. Wellcome Centre Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K. 2. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K. 3. Diabetes and Endocrinology, Department of Clinical Sciences, Lund University, Malmö, Sweden 4. Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland 5. Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland 6. Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland 7. Newcastle University, Newcastle, U.K. 8. Human Genetics Programme, Wellcome Sanger Institute, University of Cambridge, Cambridge, U.K. 9. Department of Statistics, University of Oxford, Oxford, U.K. 10. Inflammation and Immunology Research Unit, Pfizer, Berlin, Germany 11. Computational Target Validation, Pfizer, Cambridge, MA 12. Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, U.K. 13. Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland 14. Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Istituto di Ricerche Farmacologiche “Mario Negri,” Bergamo, Italy 15. Department of Paediatrics, University of Cambridge, Cambridge, U.K. 16. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH 17. Department of Family Medicine and Public Health, University of California, San Diego, San Diego, CA 18. Steno Diabetes Center Copenhagen, Gentofte, Denmark 19. Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland 20. Diabetes Center, Vaasa Health Care Center, Vaasa, Finland 21. Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan 22. Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Nishihara, Japan 23. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan 24. Department of Genomic Medicine, National Cerebral and Cardiovascular Center, Suita, Japan 25. Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan 26. Saw Swee Hock School of Public Health, National University of Singapore, Singapore 27. Division of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 28. Yong Loo Lin School of Medicine, National University of Singapore, Singapore 29. Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China 30. Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China 31. Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China 32. Integrated Bioinformatics Laboratory for Cancer and Metabolic Diseases, The Chinese University of Hong Kong, Hong Kong, China 33. Clinical Research Unit, Khoo Teck Puat Hospital, National Healthcare Group, Singapore 34. Centre for Public Health, Queen's University Belfast, Belfast, U.K. 35. Division of Nephrology and Hypertension and Diabetes & Metabolism Research Center, University of Utah Health, Salt Lake City, UT 36. Sorbonnes Université, University Pierre and Marie Curie, INSERM UMRS 1166, Institute for Cardiometabolism and Nutrition, Department of Genomics and Pathophysiology of Cardiovascular Diseases, Paris, France 37. Endocrinology-Diabetology, Centre Hospitalier Universitaire de Poitiers, Poitiers, France 38. Clinical Investigation Center 1402 and U1082, INSERM, University of Poitiers, Poitiers, France 39. Faculté de Médecine et de Pharmacie, University of Poitiers, Poitiers, France 40. Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Canada 41. The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 42. Diabetes and Cardiovascular Disease–Genetic Epidemiology, Department of Clinical Sciences, Lund University, Malmö, Sweden 43. Research Centre for Prevention and Health, Capital Region of Denmark, Glostrup, Denmark 44. Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark 45. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 46. Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark 47. Department of Public Health, Aarhus University, Aarhus, Denmark 48. Danish Diabetes Academy, Odense, Denmark 49. Department of Regional Health Research, University of Southern Denmark, Odense, Denmark 50. Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark 51. Hypertension and Cardiovascular Disease, Department of Clinical Sciences, Lund University, Malmö, Sweden 52. Diabetes Centre, Clinical Research Unit, Department of Medicine, Khoo Teck Puat Hospital, National Healthcare Group, Singapore 53. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 54. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 55. Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 56. KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Norway 57. Abdominal Center Endocrinology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland 58. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland 59. Joslin Diabetes Center, Harvard Medical School, Boston, MA 60. Center for Public Health Genomics, University of Virginia, Charlottesville, VA 61. Center for Basic and Translational Obesity Research and Division of Endocrinology, Boston Children's Hospital, Boston, MA 62. Programs in Medical and Population Genetics and Metabolism, Broad Institute, Cambridge, MA 63. Department of Genetics, Harvard Medical School, Boston, MA 64. Diabetes Clinical Research Center, Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 65. Department of Medicine, Harvard Medical School, Boston, MA 66. Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, U.K. 67. Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark 68. Unit of Nephrology and Dialysis, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy 69. Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy 70. Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Pfizer, Cambridge, MA 71. Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K. 72. Baker IDI Heart and Diabetes Institute, Melbourne, Australia 73. Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, U.K. 74. National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K.
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.
Funder
Innovative Medicine Initiative
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
Cited by
129 articles.
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