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. 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 and Cristian Pattaro
Additional contact information
Markus Scholz: Statistics and Epidemiology, University of Leipzig
Katrin Horn: Statistics and Epidemiology, University of Leipzig
Janne Pott: Statistics and Epidemiology, University of Leipzig
Matthias Wuttke: Faculty of Medicine and Medical Center–University of Freiburg
Andreas Kühnapfel: Statistics and Epidemiology, University of Leipzig
M. Kamal Nasr: University Medicine Greifswald
Holger Kirsten: Statistics and Epidemiology, University of Leipzig
Yong Li: Faculty of Medicine and Medical Center–University of Freiburg
Anselm Hoppmann: Faculty of Medicine and Medical Center–University of Freiburg
Mathias Gorski: University of Regensburg
Sahar Ghasemi: University Medicine Greifswald
Man Li: University of Utah
Adrienne Tin: University of Mississippi Medical Center
Jin-Fang Chai: National University of Singapore and National University Health System
Massimiliano Cocca: IRCCS ‘Burlo Garofolo’
Judy Wang: Washington University School of Medicine
Teresa Nutile: Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’-CNR
Masato Akiyama: RIKEN Center for Integrative Medical Sciences (IMS)
Bjørn Olav Åsvold: Norwegian University of Science and Technology
Nisha Bansal: University of Washington
Mary L. Biggs: University of Washington
Thibaud Boutin: University of Edinburgh
Hermann Brenner: German Cancer Research Center (DKFZ)
Ben Brumpton: Norwegian University of Science and Technology
Ralph Burkhardt: University of Leipzig
Jianwen Cai: University of North Carolina at Chapel Hill
Archie Campbell: University of Edinburgh
Harry Campbell: University of Edinburgh, Teviot Place
John Chalmers: University of New South Wales
Daniel I. Chasman: Brigham and Women’s Hospital
Miao Ling Chee: Singapore National Eye Center
Miao Li Chee: Singapore National Eye Center
Xu Chen: Karolinska Institutet
Ching-Yu Cheng: Singapore National Eye Center
Renata Cifkova: Charles University in Prague, First Faculty of Medicine and Thomayer University Hospital
Martha Daviglus: University of Illinois at Chicago
Graciela Delgado: University of Heidelberg
Katalin Dittrich: University of Leipzig
Todd L. Edwards: Tennessee Valley Healthcare System (626)/Vanderbilt University
Karlhans Endlich: partner site Greifswald
J. Michael Gaziano: VA Boston Healthcare System
Ayush Giri: Vanderbilt University Medical Center
Franco Giulianini: Brigham and Women’s Hospital
Scott D. Gordon: QIMR Berghofer Medical Research Institute
Daniel F. Gudbjartsson: deCODE Genetics/Amgen, Inc.
Stein Hallan: Norwegian University of Science and Technology
Pavel Hamet: Montreal University Hospital Research Center, CHUM
Catharina A. Hartman: University of Groningen, University Medical Center Groningen
Caroline Hayward: University of Edinburgh
Iris M. Heid: University of Regensburg
Jacklyn N. Hellwege: Tennessee Valley Healthcare System (626)/Vanderbilt University
Bernd Holleczek: German Cancer Research Center (DKFZ)
Hilma Holm: deCODE Genetics/Amgen, Inc.
Nina Hutri-Kähönen: Tampere University
Kristian Hveem: Norwegian University of Science and Technology
Berend Isermann: University of Leipzig
Jost B. Jonas: University Heidelberg
Peter K. Joshi: University of Edinburgh, Teviot Place
Yoichiro Kamatani: RIKEN Center for Integrative Medical Sciences (IMS)
Masahiro Kanai: RIKEN Center for Integrative Medical Sciences (IMS)
Mika Kastarinen: Finnish Medicines Agency
Chiea Chuen Khor: Agency for Science Technology and Research
Wieland Kiess: University of Leipzig
Marcus E. Kleber: University of Heidelberg
Antje Körner: University of Leipzig
Peter Kovacs: University of Leipzig
Alena Krajcoviechova: Charles University in Prague, First Faculty of Medicine and Thomayer University Hospital
Holly Kramer: Loyola University Chicago
Bernhard K. Krämer: University of Heidelberg
Mikko Kuokkanen: Finnish Institute for Health and Welfare
Mika Kähönen: Tampere University Hospital
Leslie A. Lange: University of Colorado Denver-Anschutz Medical Campus
James P. Lash: University of Illinois at Chicago
Terho Lehtimäki: Fimlab Laboratories, and The Wellbeing Services County of Pirkanmaa
Hengtong Li: National University of Singapore and National University Health System
Bridget M. Lin: University of North Carolina at Chapel Hill
Jianjun Liu: Agency for Science Technology and Research
Markus Loeffler: Statistics and Epidemiology, University of Leipzig
Leo-Pekka Lyytikäinen: Fimlab Laboratories, and The Wellbeing Services County of Pirkanmaa
Patrik K. E. Magnusson: Karolinska Institutet
Nicholas G. Martin: QIMR Berghofer Medical Research Institute
Koichi Matsuda: The University of Tokyo
Yuri Milaneschi: Amsterdam UMC/Vrije Universiteit and GGZ inGeest
Pashupati P. Mishra: Fimlab Laboratories, and The Wellbeing Services County of Pirkanmaa
Nina Mononen: Fimlab Laboratories, and The Wellbeing Services County of Pirkanmaa
Grant W. Montgomery: University of Queensland
Dennis O. Mook-Kanamori: Leiden University Medical Center
Josyf C. Mychaleckyj: University of Virginia, Charlottesville
Winfried März: University of Heidelberg
Matthias Nauck: partner site Greifswald
Kjell Nikus: Tampere University Hospital
Ilja M. Nolte: University of Groningen, University Medical Center Groningen
Raymond Noordam: Leiden University Medical Center
Yukinori Okada: RIKEN Center for Integrative Medical Sciences (IMS)
Isleifur Olafsson: Landspitali University Hospital
Albertine J. Oldehinkel: University of Groningen, University Medical Center Groningen
Brenda W. J. H. Penninx: Amsterdam UMC/Vrije Universiteit and GGZ inGeest
Markus Perola: Finnish Institute for Health and Welfare
Nicola Pirastu: University of Edinburgh, Teviot Place
Ozren Polasek: University of Split Medical School
David J. Porteous: University of Edinburgh
Tanja Poulain: University of Leipzig
Bruce M. Psaty: University of Washington
Ton J. Rabelink: Leiden University Medical Center
Laura M. Raffield: University of North Carolina
Olli T. Raitakari: University of Turku and Turku University Hospital
Humaira Rasheed: Norwegian University of Science and Technology
Dermot F. Reilly: Janssen Pharmaceuticals Inc.
Kenneth M. Rice: University of Washington
Anne Richmond: University of Edinburgh
Paul M. Ridker: Brigham and Women’s Hospital
Jerome I. Rotter: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Igor Rudan: University of Edinburgh, Teviot Place
Charumathi Sabanayagam: Singapore National Eye Center
Veikko Salomaa: Finnish Institute for Health and Welfare
Neil Schneiderman: University of Miami
Ben Schöttker: German Cancer Research Center (DKFZ)
Mario Sims: University of California at Riverside School of Medicine
Harold Snieder: University of Groningen, University Medical Center Groningen
Klaus J. Stark: University of Regensburg
Kari Stefansson: deCODE Genetics/Amgen, Inc.
Hannah Stocker: German Cancer Research Center (DKFZ)
Michael Stumvoll: University of Leipzig
Patrick Sulem: deCODE Genetics/Amgen, Inc.
Gardar Sveinbjornsson: deCODE Genetics/Amgen, Inc.
Per O. Svensson: Karolinska Institutet
E-Shyong Tai: National University of Singapore and National University Health System
Kent D. Taylor: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Bamidele O. Tayo: Loyola University Chicago
Andrej Teren: University of Leipzig
Yih-Chung Tham: Singapore National Eye Center
Joachim Thiery: University of Leipzig
Chris H. L. Thio: University of Groningen, University Medical Center Groningen
Laurent F. Thomas: Norwegian University of Science and Technology
Johanne Tremblay: Montreal University Hospital Research Center, CHUM
Anke Tönjes: University of Leipzig
Peter J. Most: University of Groningen, University Medical Center Groningen
Veronique Vitart: University of Edinburgh
Uwe Völker: partner site Greifswald
Ya Xing Wang: Capital Medical University
Chaolong Wang: Agency for Science Technology and Research
Wen Bin Wei: Capital Medical University
John B. Whitfield: QIMR Berghofer Medical Research Institute
Sarah H. Wild: University of Edinburgh, Teviot Place
James F. Wilson: University of Edinburgh
Thomas W. Winkler: University of Regensburg
Tien-Yin Wong: Singapore National Eye Center
Mark Woodward: University of New South Wales
Xueling Sim: National University of Singapore and National University Health System
Audrey Y. Chu: Genetics, Merck & Co., Inc
Mary F. Feitosa: Washington University School of Medicine
Unnur Thorsteinsdottir: deCODE Genetics/Amgen, Inc.
Adriana M. Hung: Tennessee Valley Healthcare System (626)/Vanderbilt University
Alexander Teumer: University Medicine Greifswald
Nora Franceschini: University of North Carolina at Chapel Hill
Afshin Parsa: National Institutes of Health
Anna Köttgen: Faculty of Medicine and Medical Center–University of Freiburg
Pascal Schlosser: Faculty of Medicine and Medical Center–University of Freiburg
Cristian Pattaro: Eurac Research, Institute for Biomedicine (affiliated with the University of Lübeck)

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-44709-1

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