Article open access publication

A catalog of genetic loci associated with kidney function from analyses of a million individuals

Nature Genetics, Springer Nature, ISSN 1061-4036

Volume 51, 6, 2019

DOI:10.1038/s41588-019-0407-x, Dimensions: pub.1116078524, PMC: PMC6698888, PMID: 31152163,

Authors

Li, Yong (1)
Li, Man (2)
Gorski, Mathias (5) (6)
Tin, Adrienne (7) (8)
Giri, Ayush (11) (12)
Chai, Jin-Fang (13) (14)
Ghasemi, Sahar (21) (22)
Xu, Yizhe (2)
Yu, Zhi (8)
Akiyama, Masato (25) (26)
Afaq, Saima (27) (28)
Ärnlöv, Johan (31) (32)
Bergmann, Sven (35) (36) (37)
Brenner, Hermann (44) (45)
Burkhardt, Ralph (6) (10)
Chambers, John C. (28) (48) (49)
Chen, Xu (32)
Cheng, Ching-Yu (13) (14) (50) (51)
Ciullo, Marina (17) (54)
Corre, Tanguy (36) (37) (56)
Cusi, Daniele (58) (59)
Eckardt, Kai-Uwe (65) (66)
Elliott, Paul (28) (67)
Endlich, Karlhans (21) (22)
Franco, Oscar H. (24) (69)
Froguel, Philippe (28) (41)
Gao, He (28)
Gasparini, Paolo (20) (46)
Gieger, Christian (74) (75) (76)
Girotto, Giorgia (20) (46)
Hamet, Pavel (82) (83)
Heng, Chew-Kiat (13) (14)
Huang, Wei (87) (88)
Ingelsson, Erik (73) (93)
Jonas, Jost B. (45) (95)
Kähönen, Mika (89) (90)
Kamatani, Yoichiro (26) (97)
Kanai, Masahiro (26) (99)
Khor, Chiea-Chuen (50) (64)
Koenig, Wolfgang (21) (101) (102)
Kooner, Jaspal S. (28) (49)
Kuokkanen, Mikko (105) (106)
Kuusisto, Johanna (100) (107)
Laakso, Markku (100) (107)
Lim, Su-Chi (13) (14) (109)
Lind, Lars (73)
Lindgren, Cecilia M. (110) (111)
Liu, Jun (24)
Liu, Jianjun (13) (14) (64)
März, Winfried (45) (86) (112)
Meisinger, Christa (114) (115)
Meitinger, Thomas (21) (102) (116)
Nalls, Mike A. (84) (121)
Nauck, Matthias (21) (22)
Nikus, Kjell (89) (90)
Ning, Boting (122)
Palsson, Runolfur (80) (92)
Polasek, Ozren (129) (130)
Raitakari, Olli T. (131) (132)
Ridker, Paul M. (77) (99)
Rizzi, Federica (133) (134)
Rueedi, Rico (36) (37)
Ruggiero, Daniela (17) (54)
Salvi, Erika (134) (135)
Schöttker, Ben (44) (45)
Schupf, Nicole (136) (137) (138)
Shi, Yuan (50)
Strauch, Konstantin (141) (142)
Svensson, Per O. (143) (144)
Tai, E-Shyong (13) (14) (51)
Tremblay, Johanne (83) (146)
Tzoulaki, Ioanna (28) (147)
van Dam, Rob M. (13) (14)
van der Harst, Pim (23) (148)
Völker, Uwe (21) (22)
Waldenberger, Melanie (21) (75) (76)
Wang, Chaolong (64) (149)
Wong, Charlene (13) (14)
Wong, Tien-Yin (13) (14) (50)
Xu, Liang (95)
Yang, Qiong (122)
Yasuda, Masayuki (50) (151)
Zhang, Weihua (28) (49)
Rotter, Jerome I. (145) (152)
Psaty, Bruce M. (33) (153)
Parsa, Afshin (123) (155)
Chasman, Daniel I. (77) (99)
Ho, Kevin (156) (157)
Morris, Andrew P. (55) (111)
Akilesh, Shreeram (33) (159)
Sim, Xueling (13) (14)
Böger, Carsten A. (6) (161)
Okada, Yukinori (162) (163)
Edwards, Todd L. (12) (85)
Hung, Adriana M. (12) (85)
Teumer, Alexander (21) (22)
Köttgen, Anna * (1) (8)

* Corresponding author

Affiliations

Organisations

  1. (1) University Medical Center Freiburg, grid.7708.8
  2. (2) University of Utah, grid.223827.e
  3. (3) GlaxoSmithKline (United States), grid.418019.5
  4. (4) Washington University in St. Louis, grid.4367.6
  5. (5) University of Regensburg, grid.7727.5
  6. (6) University Hospital Regensburg, grid.411941.8
  7. (7) Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, MD, USA
  8. (8) Johns Hopkins University, grid.21107.35
  9. (9) MSD (United States), grid.417993.1
  10. (10) Leipzig University, grid.9647.c
  11. (11) United States Department of Veterans Affairs, grid.418356.d
  12. (12) Vanderbilt University Medical Center, grid.412807.8
  13. (13) National University Health System, grid.410759.e
  14. (14) National University of Singapore, grid.4280.e
  15. (15) deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
  16. (16) Loyola University Chicago, grid.164971.c
  17. (17) Institute of Genetics and Biophysics, grid.419869.b
  18. (18) Eurac Research, Institute for Biomedicine (affiliated with the University of Lübeck), Bolzano, Italy
  19. (19) University of Edinburgh, grid.4305.2
  20. (20) IRCCS Materno Infantile Burlo Garofolo, grid.418712.9
  21. (21) German Centre for Cardiovascular Research, grid.452396.f
  22. (22) University of Greifswald, grid.5603.0
  23. (23) University Medical Center Groningen, grid.4494.d
  24. (24) Erasmus University Medical Center, grid.5645.2
  25. (25) Kyushu University, grid.177174.3
  26. (26) RIKEN, grid.7597.c
  27. (27) Khyber Medical University, grid.444779.d
  28. (28) Imperial College London, grid.7445.2
  29. (29) Steno Diabetes Center, grid.419658.7, Capital Region
  30. (30) Lund University, grid.4514.4
  31. (31) Dalarna University, grid.411953.b
  32. (32) Karolinska Institute, grid.4714.6
  33. (33) University of Washington, grid.34477.33
  34. (34) University Hospital of Geneva, grid.150338.c
  35. (35) University of Cape Town, grid.7836.a
  36. (36) Swiss Institute of Bioinformatics, grid.419765.8
  37. (37) University of Lausanne, grid.9851.5
  38. (38) Istituto di Genetica Molecolare, grid.419479.6
  39. (39) University of Michigan, grid.214458.e
  40. (40) The University of Texas Health Science Center at Houston, grid.267308.8
  41. (41) Integrated Genomics and Metabolic Diseases Modeling, grid.463858.4
  42. (42) University of Potsdam, grid.11348.3f
  43. (43) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  44. (44) German Cancer Research Center, grid.7497.d
  45. (45) Heidelberg University, grid.7700.0
  46. (46) University of Trieste, grid.5133.4
  47. (47) University of Cambridge, grid.5335.0
  48. (48) Nanyang Technological University, grid.59025.3b
  49. (49) Ealing Hospital, grid.415918.0
  50. (50) Singapore National Eye Center, grid.419272.b
  51. (51) Duke NUS Graduate Medical School, grid.428397.3
  52. (52) University of Southern Denmark, grid.10825.3e, SDU
  53. (53) Charles University, grid.4491.8
  54. (54) Istituto Neurologico Mediterraneo, grid.419543.e
  55. (55) University of Liverpool, grid.10025.36
  56. (56) Institute of Social and Preventive Medicine, grid.482968.9
  57. (57) San Raffaele Research Institute, Milan, Italy
  58. (58) Bio4Dreams–Business Nursery for Life Sciences, Milan, Italy
  59. (59) Institute of Biomedical Technologies, grid.429135.8
  60. (60) Leiden University Medical Center, grid.10419.3d
  61. (61) Kiel University, grid.9764.c
  62. (62) NHS Blood and Transplant, grid.436365.1
  63. (63) Wake Forest University, grid.241167.7
  64. (64) Genome Institute of Singapore, grid.418377.e
  65. (65) Charité, grid.6363.0
  66. (66) University of Erlangen-Nuremberg, grid.5330.5
  67. (67) Health Data Research UK–London, London, UK
  68. (68) National Institute on Aging, grid.419475.a
  69. (69) University of Bern, grid.5734.5
  70. (70) Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein, Kiel, Germany
  71. (71) Hebrew University of Jerusalem, grid.9619.7
  72. (72) VA Boston Healthcare System, grid.410370.1
  73. (73) Uppsala University, grid.8993.b
  74. (74) German Center for Diabetes Research, grid.452622.5
  75. (75) Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
  76. (76) Institute of Epidemiology, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany
  77. (77) Brigham and Women's Hospital, grid.62560.37
  78. (78) QIMR Berghofer Medical Research Institute, grid.1049.c
  79. (79) Icelandic Heart Association, grid.420802.c
  80. (80) University of Iceland, grid.14013.37
  81. (81) University of Tartu, grid.10939.32
  82. (82) Medpharmgene, Montreal, Quebec, Canada
  83. (83) Centre Hospitalier de l’Université de Montréal, grid.410559.c
  84. (84) National Institutes of Health, grid.94365.3d
  85. (85) Vanderbilt University, grid.152326.1
  86. (86) Medical University of Graz, grid.11598.34
  87. (87) Chinese National Human Genome Center, grid.418564.a
  88. (88) Shanghai Industrial Technology Institute, grid.495809.9
  89. (89) Tampere University, grid.502801.e
  90. (90) Tampere University Hospital, grid.412330.7
  91. (91) National Heart Lung and Blood Institute, grid.279885.9
  92. (92) National University Hospital of Iceland, grid.410540.4
  93. (93) Stanford University, grid.168010.e
  94. (94) Max Planck Institute of Psychiatry, grid.419548.5
  95. (95) Capital Medical University, grid.24696.3f
  96. (96) Geisinger Research, Biomedical and Translational Informatics Institute, Rockville, MD, USA
  97. (97) Kyoto University, grid.258799.8
  98. (98) University of Pittsburgh, grid.21925.3d
  99. (99) Harvard University, grid.38142.3c
  100. (100) Kuopio University Hospital, grid.410705.7
  101. (101) University of Ulm, grid.6582.9
  102. (102) Technical University of Munich, grid.6936.a
  103. (103) Innsbruck Medical University, grid.5361.1
  104. (104) RIKEN Center for Integrative Medical Sciences (IMS), Yokohama (Kanagawa), Japan
  105. (105) University of Helsinki, grid.7737.4
  106. (106) National Institute for Health and Welfare, grid.14758.3f
  107. (107) University of Eastern Finland, grid.9668.1
  108. (108) University of Colorado Anschutz Medical Campus, grid.430503.1
  109. (109) Khoo Teck Puat Hospital, grid.415203.1
  110. (110) Broad Institute, grid.66859.34
  111. (111) University of Oxford, grid.4991.5
  112. (112) Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany
  113. (113) University of Tokyo, grid.26999.3d
  114. (114) Chair of Epidemiology, Ludwig- Maximilians-Universität München at UNIKA-T Augsburg, Augsburg, Germany
  115. (115) Helmholtz Zentrum München, grid.4567.0
  116. (116) Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
  117. (117) VU University Medical Center, grid.16872.3a
  118. (118) University of North Carolina at Chapel Hill, grid.10698.36
  119. (119) University of Queensland, grid.1003.2
  120. (120) University of Virginia, grid.27755.32
  121. (121) Data Tecnica International, Glen Echo, MD, USA
  122. (122) Boston University, grid.189504.1
  123. (123) University of Maryland, Baltimore, grid.411024.2
  124. (124) Thrombolysis in Myocardial Infarction Study Group, grid.492942.0
  125. (125) University of Glasgow, grid.8756.c
  126. (126) Boston Medical Center, grid.239424.a
  127. (127) Institute of Genetic and Biomedical Research, grid.428485.7
  128. (128) University Hospital of Lausanne, grid.8515.9
  129. (129) Gen-info Ltd, Zagreb, Croatia
  130. (130) University of Split, grid.38603.3e
  131. (131) Turku University Hospital, grid.410552.7
  132. (132) University of Turku, grid.1374.1
  133. (133) ePhood Scientific Unit, ePhood SRL, Milano, Italy
  134. (134) University of Milan, grid.4708.b
  135. (135) Carlo Besta Neurological Institute, grid.417894.7
  136. (136) Columbia University, grid.21729.3f
  137. (137) Columbia University Medical Center, grid.239585.0
  138. (138) Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA
  139. (139) Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
  140. (140) Wellcome Sanger Institute, grid.10306.34
  141. (141) Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
  142. (142) Ludwig Maximilian University of Munich, grid.5252.0
  143. (143) Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden
  144. (144) Stockholm South General Hospital, grid.416648.9
  145. (145) Los Angeles Biomedical Research Institute, grid.279946.7
  146. (146) CRCHUM, Montreal, Canada
  147. (147) University of Ioannina, grid.9594.1
  148. (148) Netherlands Heart Institute, grid.411737.7
  149. (149) Huazhong University of Science and Technology, grid.33199.31
  150. (150) University of Auckland, grid.9654.e
  151. (151) Tohoku University, grid.69566.3a
  152. (152) Harbor–UCLA Medical Center, grid.239844.0
  153. (153) Kaiser Permanente Washington Health Research Institute, grid.488833.c
  154. (154) University of Mississippi Medical Center, grid.410721.1
  155. (155) National Institute of Diabetes and Digestive and Kidney Diseases, grid.419635.c
  156. (156) Department of Nephrology, Geisinger, Danville, PA, USA
  157. (157) Kidney Health Research Institute (KHRI), Geisinger, Danville, PA, USA
  158. (158) University of Zurich, grid.7400.3
  159. (159) University of Washington Medical Center, grid.412623.0
  160. (160) Geisinger Research, Biomedical and Translational Informatics Institute, Danville, PA, USA
  161. (161) Department of Nephrology and Rheumatology, Kliniken Südostbayern, Regensburg, Germany
  162. (162) Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences (IMS), Osaka, Japan
  163. (163) Osaka University, grid.136593.b

Description

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.

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Green, Accepted