X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

Markus Scholz; Katrin Horn; Janne Pott; Matthias Wuttke; Andreas Kühnapfel; M Kamal Nasr; Holger Kirsten; Yong Li; Anselm Hoppmann; Mathias Gorski; Sahar Ghasemi; Man Li; Adrienne Tin; Jin-Fang Chai; Massimiliano Cocca; Judy Wang; Teresa Nutile; Masato Akiyama; Bjørn Olav Åsvold; Nisha Bansal; Mary L Biggs; Thibaud Boutin; Hermann Brenner; Ben Brumpton; Ralph Burkhardt; Jianwen Cai; Archie Campbell; Harry Campbell; John Chalmers; Daniel I Chasman; Miao Ling Chee; Miao Li Chee; Xu Chen; Ching-Yu Cheng; Renata Cifkova; Martha Daviglus; Graciela Delgado; Katalin Dittrich; Todd L Edwards; Karlhans Endlich; J Michael Gaziano; Ayush Giri; Franco Giulianini; Scott D Gordon; Daniel F Gudbjartsson; Stein Hallan; Pavel Hamet; Catharina A Hartman; Caroline Hayward; Iris M Heid; Jacklyn N Hellwege; Bernd Holleczek; Hilma Holm; Nina Hutri-Kähönen; Kristian Hveem; Berend Isermann; Jost B Jonas; Peter K Joshi; Yoichiro Kamatani; Masahiro Kanai; Mika Kastarinen; Chiea Chuen Khor; Wieland Kiess; Marcus E Kleber; Antje Körner; Peter Kovacs; Alena Krajcoviechova; Holly Kramer; Bernhard K Krämer; Mikko Kuokkanen; Mika Kähönen; Leslie A Lange; James P Lash; Terho Lehtimäki; Hengtong Li; Bridget M Lin; Jianjun Liu; Markus Loeffler; Leo-Pekka Lyytikäinen; Patrik K E Magnusson; Nicholas G Martin; Koichi Matsuda; Yuri Milaneschi; Pashupati P Mishra; Nina Mononen; Grant W Montgomery; Dennis O Mook-Kanamori; Josyf C Mychaleckyj; Winfried März; Matthias Nauck; Kjell Nikus; Ilja M Nolte; Raymond Noordam; Yukinori Okada; Isleifur Olafsson; Albertine J Oldehinkel; Brenda W J H Penninx; Markus Perola; Nicola Pirastu; Ozren Polasek; David J Porteous; Tanja Poulain; Bruce M Psaty; Ton J Rabelink; Laura M Raffield; Olli T Raitakari; Humaira Rasheed; Dermot F Reilly; Kenneth M Rice; Anne Richmond; Paul M Ridker; Jerome I Rotter; Igor Rudan; Charumathi Sabanayagam; Veikko Salomaa; Neil Schneiderman; Ben Schöttker; Mario Sims; Harold Snieder; Klaus J Stark; Kari Stefansson; Hannah Stocker; Michael Stumvoll; Patrick Sulem; Gardar Sveinbjornsson; Per O Svensson; E-Shyong Tai; Kent D Taylor; Bamidele O Tayo; Andrej Teren; Yih-Chung Tham; Joachim Thiery; Chris H L Thio; Laurent F Thomas; Johanne Tremblay; Anke Tönjes; Peter J van der Most; Veronique Vitart; Uwe Völker; Ya Xing Wang; Chaolong Wang; Wen Bin Wei; John B Whitfield; Sarah H Wild; James F Wilson; Thomas W Winkler; Tien-Yin Wong; Mark Woodward; Xueling Sim; Audrey Y Chu; Mary F Feitosa; Unnur Thorsteinsdottir; Adriana M Hung; Alexander Teumer; Nora Franceschini; Afshin Parsa; Anna Köttgen; Pascal Schlosser; Cristian Pattaro

doi:10.1038/s41467-024-44709-1

X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

Nat Commun. 2024 Jan 18;15(1):586. doi: 10.1038/s41467-024-44709-1.

Authors

Markus Scholz^#^{1

2}, Katrin Horn^#^{3

4}, Janne Pott^{3

4}, Matthias Wuttke^{5

6}, Andreas Kühnapfel^{3

4}, M Kamal Nasr^{7

8

9}, Holger Kirsten^{3

4}, Yong Li⁵, Anselm Hoppmann⁵, Mathias Gorski^{10

11}, Sahar Ghasemi^{7

8}, Man Li¹², Adrienne Tin^{13

14}, Jin-Fang Chai¹⁵, Massimiliano Cocca¹⁶, Judy Wang¹⁷, Teresa Nutile¹⁸, Masato Akiyama^{19

20}, Bjørn Olav Åsvold^{21

22}, Nisha Bansal^{23

24}, Mary L Biggs^{25

26}, Thibaud Boutin²⁷, Hermann Brenner^{28

29}, Ben Brumpton^{21

30

31}, Ralph Burkhardt^{4

32}, Jianwen Cai³³, Archie Campbell³⁴, Harry Campbell³⁵, John Chalmers³⁶, Daniel I Chasman^{37

38}, Miao Ling Chee³⁹, Miao Li Chee³⁹, Xu Chen⁴⁰, Ching-Yu Cheng^{39

41

42}, Renata Cifkova^{43

44}, Martha Daviglus⁴⁵, Graciela Delgado⁴⁶, Katalin Dittrich⁴⁷, Todd L Edwards^{48

49}, Karlhans Endlich^{8

50}, J Michael Gaziano⁵¹, Ayush Giri^{52

53}, Franco Giulianini³⁷, Scott D Gordon⁵⁴, Daniel F Gudbjartsson^{55

56}, Stein Hallan^{57

58}, Pavel Hamet^{59

60}, Catharina A Hartman⁶¹, Caroline Hayward²⁷, Iris M Heid¹⁰, Jacklyn N Hellwege^{48

49

62}, Bernd Holleczek²⁸, Hilma Holm⁵⁵, Nina Hutri-Kähönen⁶³, Kristian Hveem²¹, Berend Isermann^{4

64}, Jost B Jonas^{65

66

67

68}, Peter K Joshi³⁵, Yoichiro Kamatani^{19

69}, Masahiro Kanai^{19

70

71}, Mika Kastarinen⁷², Chiea Chuen Khor^{73

74}, Wieland Kiess^{4

47}, Marcus E Kleber^{46

75}, Antje Körner^{4

47

76}, Peter Kovacs⁷⁷, Alena Krajcoviechova⁴³, Holly Kramer^{78

79}, Bernhard K Krämer⁴⁶, Mikko Kuokkanen^{80

81

82}, Mika Kähönen^{83

84}, Leslie A Lange⁸⁵, James P Lash⁸⁶, Terho Lehtimäki^{87

88}, Hengtong Li⁴², Bridget M Lin³³, Jianjun Liu^{73

89}, Markus Loeffler^{3

4}, Leo-Pekka Lyytikäinen^{87

88}, Patrik K E Magnusson⁴⁰, Nicholas G Martin⁵⁴, Koichi Matsuda⁹⁰, Yuri Milaneschi⁹¹, Pashupati P Mishra^{87

88}, Nina Mononen^{87

88}, Grant W Montgomery⁹², Dennis O Mook-Kanamori^{93

94}, Josyf C Mychaleckyj⁹⁵, Winfried März^{46

96

97}, Matthias Nauck^{8

98}, Kjell Nikus^{99

100}, Ilja M Nolte¹⁰¹, Raymond Noordam¹⁰², Yukinori Okada^{103

104

105}, Isleifur Olafsson¹⁰⁶, Albertine J Oldehinkel⁶¹, Brenda W J H Penninx⁹¹, Markus Perola^{80

81}, Nicola Pirastu^{35

107}, Ozren Polasek¹⁰⁸, David J Porteous³⁴, Tanja Poulain^{4

47}, Bruce M Psaty¹⁰⁹, Ton J Rabelink^{110

111}, Laura M Raffield¹¹², Olli T Raitakari^{113

114

115}, Humaira Rasheed^{21

30

116}, Dermot F Reilly¹¹⁷, Kenneth M Rice²⁶, Anne Richmond²⁷, Paul M Ridker^{37

38}, Jerome I Rotter¹¹⁸, Igor Rudan³⁵, Charumathi Sabanayagam^{39

41}, Veikko Salomaa⁸⁰, Neil Schneiderman¹¹⁹, Ben Schöttker^{28

29}, Mario Sims¹²⁰, Harold Snieder¹⁰¹, Klaus J Stark¹⁰, Kari Stefansson^{55

121}, Hannah Stocker^{28

29}, Michael Stumvoll⁷⁷, Patrick Sulem⁵⁵, Gardar Sveinbjornsson⁵⁵, Per O Svensson^{122

123}, E-Shyong Tai^{15

89

124}, Kent D Taylor¹¹⁸, Bamidele O Tayo⁷⁸, Andrej Teren^{4

125}, Yih-Chung Tham^{39

42}, Joachim Thiery^{4

64}, Chris H L Thio¹⁰¹, Laurent F Thomas^{21

126

127

128}, Johanne Tremblay⁵⁹, Anke Tönjes⁷⁷, Peter J van der Most¹⁰¹, Veronique Vitart²⁷, Uwe Völker^{8

129}, Ya Xing Wang⁶⁶, Chaolong Wang^{73

130}, Wen Bin Wei¹³¹, John B Whitfield⁵⁴, Sarah H Wild¹³², James F Wilson^{27

35}, Thomas W Winkler¹⁰, Tien-Yin Wong^{39

41

133}, Mark Woodward^{36

134}, Xueling Sim¹⁵, Audrey Y Chu¹³⁵, Mary F Feitosa¹⁷, Unnur Thorsteinsdottir^{55

121}, Adriana M Hung^{48

136}, Alexander Teumer^{7

8

9

137}, Nora Franceschini¹³⁸, Afshin Parsa¹³⁹, Anna Köttgen^{5

140}, Pascal Schlosser^{5

140}, Cristian Pattaro¹⁴¹

Affiliations

¹ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. markus.scholz@imise.uni-leipzig.de.
² LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany. markus.scholz@imise.uni-leipzig.de.
³ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
⁴ LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
⁵ Institute of Genetic Epidemiology, Department of Data Driven Medicine, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany.
⁶ Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
⁷ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁸ DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
⁹ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
¹⁰ Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
¹¹ Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.
¹² Division of Nephrology and Hypertension, Department of Medicine, University of Utah, Salt Lake City, UT, USA.
¹³ Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁴ Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁵ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
¹⁶ Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy.
¹⁷ Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
¹⁸ Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso'-CNR, Naples, Italy.
¹⁹ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan.
²⁰ Department of Ocular Pathology and Imaging Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
²¹ K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health, Norwegian University of Science and Technology, Trondheim, Norway.
²² Department of Endocrinology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
²³ Division of Nephrology, University of Washington, Seattle, WA, USA.
²⁴ Kidney Research Institute, University of Washington, Seattle, WA, USA.
²⁵ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁶ Department of Biostatistics, University of Washington, Seattle, WA, USA.
²⁷ Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK.
²⁸ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁹ Network Aging Research, Heidelberg University, Heidelberg, Germany.
³⁰ MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
³¹ Clinic of Thoracic and Occupational Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
³² Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany.
³³ Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁴ Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK.
³⁵ Centre for Global Health, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland.
³⁶ The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
³⁷ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³⁸ Harvard Medical School, Boston, MA, USA.
³⁹ Singapore Eye Research Institute, Singapore National Eye Center, Singapore, Singapore.
⁴⁰ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
⁴¹ Ophthalmology and Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore.
⁴² Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore.
⁴³ Center for Cardiovascular Prevention, Charles University in Prague, First Faculty of Medicine and Thomayer University Hospital, Prague, Czech Republic.
⁴⁴ Department of Medicine II, Charles University in Prague, First Faculty of Medicine, Prague, Czech Republic.
⁴⁵ Institute for Minority Health Research, University of Illinois at Chicago, Chicago, IL, USA.
⁴⁶ Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
⁴⁷ University Hospital for Children and Adolescents, Pediatric Research Unit, Medical Faculty, University Medical Center, University of Leipzig, Leipzig, Germany.
⁴⁸ Department of Veteran's Affairs, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.
⁴⁹ Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵⁰ Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.
⁵¹ Massachusetts Veterans Epidemiology Research and Information Center, VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA.
⁵² Division of Quantitative Sciences, Department of Obstetrics & Gynecology, Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵³ Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.
⁵⁴ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁵⁵ deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
⁵⁶ Iceland School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
⁵⁷ Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
⁵⁸ Department of Nephrology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁵⁹ Montreal University Hospital Research Center, CHUM, Montréal, QC, Canada.
⁶⁰ Medpharmgene, Montreal, QC, Canada.
⁶¹ Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁶² Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁶³ Tampere Centre for Skills Training and Simulation, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
⁶⁴ Institute for Laboratory Medicine, University of Leipzig, Leipzig, Germany.
⁶⁵ Department of Ophthalmology, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany.
⁶⁶ Beijing Institute of Ophthalmology, Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
⁶⁷ Institute of Molecular and Clinical Ophthalmology, Basel, Switzerland.
⁶⁸ Privatpraxis Prof Jonas und Dr Panda-Jonas, Heidelberg, Germany.
⁶⁹ Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁷⁰ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁷¹ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁷² Finnish Medicines Agency, Kuopio, Finland.
⁷³ Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore.
⁷⁴ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore.
⁷⁵ SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany.
⁷⁶ Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany.
⁷⁷ Department of Medicine, University of Leipzig, Leipzig, Germany.
⁷⁸ Department of Public Health Sciences, Loyola University Chicago, Maywood, IL, USA.
⁷⁹ Division of Nephrology and Hypertension, Loyola University Chicago, Chicago, IL, USA.
⁸⁰ Finnish Institute for Health and Welfare, Helsinki, Finland.
⁸¹ Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁸² Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
⁸³ Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland.
⁸⁴ Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
⁸⁵ Division of Biomedical Informatics and Personalized Medicine, School of Medicine, University of Colorado Denver-Anschutz Medical Campus, Aurora, CO, USA.
⁸⁶ Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
⁸⁷ Department of Clinical Chemistry, Fimlab Laboratories, and The Wellbeing Services County of Pirkanmaa, Tampere, Finland.
⁸⁸ Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
⁸⁹ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore.
⁹⁰ Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁹¹ Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC/Vrije Universiteit and GGZ inGeest, Amsterdam, the Netherlands.
⁹² University of Queensland, Brisbane, QLD, Australia.
⁹³ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
⁹⁴ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
⁹⁵ Center for Public Health Genomics, University of Virginia, Charlottesville, Charlottesville, VA, USA.
⁹⁶ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Graz, Austria.
⁹⁷ Synlab Academy, Synlab Holding Deutschland GmbH, Augsburg, Germany.
⁹⁸ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
⁹⁹ Department of Cardiology, Heart Center, Tampere University Hospital, Tampere, Finland.
¹⁰⁰ Department of Cardiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
¹⁰¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁰² Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
¹⁰³ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan.
¹⁰⁴ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
¹⁰⁵ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
¹⁰⁶ Department of Clinical Biochemistry, Landspitali University Hospital, Reykjavik, Iceland.
¹⁰⁷ Biostatistics Unit - Population and Medical Genomics Programme, Genomics Research Centre, Human Technopole Palazzo Italia, Viale Rita Levi‑Montalcini, 1, 20157, Milan, Italy.
¹⁰⁸ University of Split Medical School, Split, Croatia.
¹⁰⁹ Cardiovascular Health Research Unit, Department of Medicine, Department of Epidemiology, Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
¹¹⁰ Department of Internal Medicine, Section of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
¹¹¹ Einthoven Laboratory of Experimental Vascular Research, Leiden University Medical Center, Leiden, the Netherlands.
¹¹² Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
¹¹³ Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
¹¹⁴ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
¹¹⁵ Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
¹¹⁶ Division of Medicine and Laboratory Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
¹¹⁷ Janssen Pharmaceuticals Inc., Titusville, NJ, 08560, USA.
¹¹⁸ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹¹⁹ Department of Psychology, University of Miami, Coral Gables, FL, USA.
¹²⁰ Department of Social Medicine, Population and Public Health, University of California at Riverside School of Medicine, Riverside, CA, USA.
¹²¹ Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
¹²² Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
¹²³ Department of Cardiology, Södersjukhuset, Stockholm, Sweden.
¹²⁴ Duke-NUS Medical School, Singapore, Singapore.
¹²⁵ Department of Cardiology and Intensive Care Medicine, University Hospital OWL of Bielefeld University, Campus Klinikum Bielefeld, Teutoburger Straße 50, 33604, Bielefeld, Germany.
¹²⁶ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
¹²⁷ BioCore - Bioinformatics Core Facility, Norwegian University of Science and Technology, Trondheim, Norway.
¹²⁸ Clinic of Laboratory Medicine, St.Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
¹²⁹ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
¹³⁰ School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹³¹ Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
¹³² Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland.
¹³³ Tsinghua Medicine, Tsinghua University, Beijing, China.
¹³⁴ The George Institute for Global Health, School of Public Health, Imperial College London, London, UK.
¹³⁵ Genetics, Merck & Co., Inc, Kenilworth, NJ, USA.
¹³⁶ Vanderbilt University Medical Center, Division of Nephrology & Hypertension, Nashville, TN, USA.
¹³⁷ Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, Poland.
¹³⁸ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³⁹ Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
¹⁴⁰ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁴¹ Eurac Research, Institute for Biomedicine (affiliated with the University of Lübeck), Bolzano, Italy.

^# Contributed equally.

Abstract

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Publication types

Meta-Analysis

MeSH terms

Androgens* / genetics
Chromosomes, Human, X / genetics
Female
Genetic Predisposition to Disease
Genome-Wide Association Study*
Humans
Kidney
Male
Polymorphism, Single Nucleotide
Response Elements
Tetraspanins / genetics

Substances

Androgens
TSPAN6 protein, human
Tetraspanins

Abstract

Publication types

MeSH terms

Substances

Grants and funding