Nature Communications (Jan 2024)
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
Affiliations
- Markus Scholz
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig
- Katrin Horn
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig
- Janne Pott
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig
- Matthias Wuttke
- Institute of Genetic Epidemiology, Department of Data Driven Medicine, Faculty of Medicine and Medical Center–University of Freiburg
- Andreas Kühnapfel
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig
- M. Kamal Nasr
- Institute for Community Medicine, University Medicine Greifswald
- Holger Kirsten
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig
- Yong Li
- Institute of Genetic Epidemiology, Department of Data Driven Medicine, Faculty of Medicine and Medical Center–University of Freiburg
- Anselm Hoppmann
- Institute of Genetic Epidemiology, Department of Data Driven Medicine, Faculty of Medicine and Medical Center–University of Freiburg
- Mathias Gorski
- Department of Genetic Epidemiology, University of Regensburg
- Sahar Ghasemi
- Institute for Community Medicine, University Medicine Greifswald
- Man Li
- Division of Nephrology and Hypertension, Department of Medicine, University of Utah
- Adrienne Tin
- Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center
- Jin-Fang Chai
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
- Massimiliano Cocca
- Institute for Maternal and Child Health, IRCCS ‘Burlo Garofolo’
- Judy Wang
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine
- Teresa Nutile
- Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’-CNR
- Masato Akiyama
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences (IMS)
- Bjørn Olav Åsvold
- K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health, Norwegian University of Science and Technology
- Nisha Bansal
- Division of Nephrology, University of Washington
- Mary L. Biggs
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Thibaud Boutin
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh
- Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)
- Ben Brumpton
- K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health, Norwegian University of Science and Technology
- Ralph Burkhardt
- LIFE Research Center for Civilization Diseases, University of Leipzig
- Jianwen Cai
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill
- Archie Campbell
- Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh
- Harry Campbell
- Centre for Global Health, Usher Institute, University of Edinburgh, Teviot Place
- John Chalmers
- The George Institute for Global Health, University of New South Wales
- Daniel I. Chasman
- Division of Preventive Medicine, Brigham and Women’s Hospital
- Miao Ling Chee
- Singapore Eye Research Institute, Singapore National Eye Center
- Miao Li Chee
- Singapore Eye Research Institute, Singapore National Eye Center
- Xu Chen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Ching-Yu Cheng
- Singapore Eye Research Institute, Singapore National Eye Center
- Renata Cifkova
- Center for Cardiovascular Prevention, Charles University in Prague, First Faculty of Medicine and Thomayer University Hospital
- Martha Daviglus
- Institute for Minority Health Research, University of Illinois at Chicago
- Graciela Delgado
- Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg
- Katalin Dittrich
- University Hospital for Children and Adolescents, Pediatric Research Unit, Medical Faculty, University Medical Center, University of Leipzig
- Todd L. Edwards
- Department of Veteran’s Affairs, Tennessee Valley Healthcare System (626)/Vanderbilt University
- Karlhans Endlich
- DZHK (German Center for Cardiovascular Research), partner site Greifswald
- J. Michael Gaziano
- Massachusetts Veterans Epidemiology Research and Information Center, VA Cooperative Studies Program, VA Boston Healthcare System
- Ayush Giri
- Division of Quantitative Sciences, Department of Obstetrics & Gynecology, Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University Medical Center
- Franco Giulianini
- Division of Preventive Medicine, Brigham and Women’s Hospital
- Scott D. Gordon
- QIMR Berghofer Medical Research Institute
- Daniel F. Gudbjartsson
- deCODE Genetics/Amgen, Inc.
- Stein Hallan
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology
- Pavel Hamet
- Montreal University Hospital Research Center, CHUM
- Catharina A. Hartman
- Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Department of Psychiatry, University of Groningen, University Medical Center Groningen
- Caroline Hayward
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh
- Iris M. Heid
- Department of Genetic Epidemiology, University of Regensburg
- Jacklyn N. Hellwege
- Department of Veteran’s Affairs, Tennessee Valley Healthcare System (626)/Vanderbilt University
- Bernd Holleczek
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)
- Hilma Holm
- deCODE Genetics/Amgen, Inc.
- Nina Hutri-Kähönen
- Tampere Centre for Skills Training and Simulation, Faculty of Medicine and Health Technology, Tampere University
- Kristian Hveem
- K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health, Norwegian University of Science and Technology
- Berend Isermann
- LIFE Research Center for Civilization Diseases, University of Leipzig
- Jost B. Jonas
- Department of Ophthalmology, Medical Faculty Mannheim, University Heidelberg
- Peter K. Joshi
- Centre for Global Health, Usher Institute, University of Edinburgh, Teviot Place
- Yoichiro Kamatani
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences (IMS)
- Masahiro Kanai
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences (IMS)
- Mika Kastarinen
- Finnish Medicines Agency
- Chiea Chuen Khor
- Genome Institute of Singapore, Agency for Science Technology and Research
- Wieland Kiess
- LIFE Research Center for Civilization Diseases, University of Leipzig
- Marcus E. Kleber
- Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg
- Antje Körner
- LIFE Research Center for Civilization Diseases, University of Leipzig
- Peter Kovacs
- Department of Medicine, University of Leipzig
- Alena Krajcoviechova
- Center for Cardiovascular Prevention, Charles University in Prague, First Faculty of Medicine and Thomayer University Hospital
- Holly Kramer
- Department of Public Health Sciences, Loyola University Chicago
- Bernhard K. Krämer
- Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg
- Mikko Kuokkanen
- Finnish Institute for Health and Welfare
- Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital
- Leslie A. Lange
- Division of Biomedical Informatics and Personalized Medicine, School of Medicine, University of Colorado Denver-Anschutz Medical Campus
- James P. Lash
- Department of Medicine, University of Illinois at Chicago
- Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, and The Wellbeing Services County of Pirkanmaa
- Hengtong Li
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System
- Bridget M. Lin
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill
- Jianjun Liu
- Genome Institute of Singapore, Agency for Science Technology and Research
- Markus Loeffler
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig
- Leo-Pekka Lyytikäinen
- Department of Clinical Chemistry, Fimlab Laboratories, and The Wellbeing Services County of Pirkanmaa
- Patrik K. E. Magnusson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Nicholas G. Martin
- QIMR Berghofer Medical Research Institute
- Koichi Matsuda
- Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo
- Yuri Milaneschi
- Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC/Vrije Universiteit and GGZ inGeest
- Pashupati P. Mishra
- Department of Clinical Chemistry, Fimlab Laboratories, and The Wellbeing Services County of Pirkanmaa
- Nina Mononen
- Department of Clinical Chemistry, Fimlab Laboratories, and The Wellbeing Services County of Pirkanmaa
- Grant W. Montgomery
- University of Queensland
- Dennis O. Mook-Kanamori
- Department of Clinical Epidemiology, Leiden University Medical Center
- Josyf C. Mychaleckyj
- Center for Public Health Genomics, University of Virginia, Charlottesville
- Winfried März
- Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg
- Matthias Nauck
- DZHK (German Center for Cardiovascular Research), partner site Greifswald
- Kjell Nikus
- Department of Cardiology, Heart Center, Tampere University Hospital
- Ilja M. Nolte
- Department of Epidemiology, University of Groningen, University Medical Center Groningen
- Raymond Noordam
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center
- Yukinori Okada
- Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences (IMS)
- Isleifur Olafsson
- Department of Clinical Biochemistry, Landspitali University Hospital
- Albertine J. Oldehinkel
- Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Department of Psychiatry, University of Groningen, University Medical Center Groningen
- Brenda W. J. H. Penninx
- Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC/Vrije Universiteit and GGZ inGeest
- Markus Perola
- Finnish Institute for Health and Welfare
- Nicola Pirastu
- Centre for Global Health, Usher Institute, University of Edinburgh, Teviot Place
- Ozren Polasek
- University of Split Medical School
- David J. Porteous
- Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh
- Tanja Poulain
- LIFE Research Center for Civilization Diseases, University of Leipzig
- Bruce M. Psaty
- Cardiovascular Health Research Unit, Department of Medicine, Department of Epidemiology, Department of Health Systems and Population Health, University of Washington
- Ton J. Rabelink
- Department of Internal Medicine, Section of Nephrology, Leiden University Medical Center
- Laura M. Raffield
- Department of Genetics, University of North Carolina
- Olli T. Raitakari
- Centre for Population Health Research, University of Turku and Turku University Hospital
- Humaira Rasheed
- K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health, Norwegian University of Science and Technology
- Dermot F. Reilly
- Janssen Pharmaceuticals Inc.
- Kenneth M. Rice
- Department of Biostatistics, University of Washington
- Anne Richmond
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh
- Paul M. Ridker
- Division of Preventive Medicine, Brigham and Women’s Hospital
- Jerome I. Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Igor Rudan
- Centre for Global Health, Usher Institute, University of Edinburgh, Teviot Place
- Charumathi Sabanayagam
- Singapore Eye Research Institute, Singapore National Eye Center
- Veikko Salomaa
- Finnish Institute for Health and Welfare
- Neil Schneiderman
- Department of Psychology, University of Miami
- Ben Schöttker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)
- Mario Sims
- Department of Social Medicine, Population and Public Health, University of California at Riverside School of Medicine
- Harold Snieder
- Department of Epidemiology, University of Groningen, University Medical Center Groningen
- Klaus J. Stark
- Department of Genetic Epidemiology, University of Regensburg
- Kari Stefansson
- deCODE Genetics/Amgen, Inc.
- Hannah Stocker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)
- Michael Stumvoll
- Department of Medicine, University of Leipzig
- Patrick Sulem
- deCODE Genetics/Amgen, Inc.
- Gardar Sveinbjornsson
- deCODE Genetics/Amgen, Inc.
- Per O. Svensson
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet
- E-Shyong Tai
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
- Kent D. Taylor
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Bamidele O. Tayo
- Department of Public Health Sciences, Loyola University Chicago
- Andrej Teren
- LIFE Research Center for Civilization Diseases, University of Leipzig
- Yih-Chung Tham
- Singapore Eye Research Institute, Singapore National Eye Center
- Joachim Thiery
- LIFE Research Center for Civilization Diseases, University of Leipzig
- Chris H. L. Thio
- Department of Epidemiology, University of Groningen, University Medical Center Groningen
- Laurent F. Thomas
- K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health, Norwegian University of Science and Technology
- Johanne Tremblay
- Montreal University Hospital Research Center, CHUM
- Anke Tönjes
- Department of Medicine, University of Leipzig
- Peter J. van der Most
- Department of Epidemiology, University of Groningen, University Medical Center Groningen
- Veronique Vitart
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh
- Uwe Völker
- DZHK (German Center for Cardiovascular Research), partner site Greifswald
- Ya Xing Wang
- Beijing Institute of Ophthalmology, Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical University
- Chaolong Wang
- Genome Institute of Singapore, Agency for Science Technology and Research
- Wen Bin Wei
- Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University
- John B. Whitfield
- QIMR Berghofer Medical Research Institute
- Sarah H. Wild
- Usher Institute, University of Edinburgh, Teviot Place
- James F. Wilson
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh
- Thomas W. Winkler
- Department of Genetic Epidemiology, University of Regensburg
- Tien-Yin Wong
- Singapore Eye Research Institute, Singapore National Eye Center
- Mark Woodward
- The George Institute for Global Health, University of New South Wales
- Xueling Sim
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
- Audrey Y. Chu
- Genetics, Merck & Co., Inc
- Mary F. Feitosa
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine
- Unnur Thorsteinsdottir
- deCODE Genetics/Amgen, Inc.
- Adriana M. Hung
- Department of Veteran’s Affairs, Tennessee Valley Healthcare System (626)/Vanderbilt University
- Alexander Teumer
- Institute for Community Medicine, University Medicine Greifswald
- Nora Franceschini
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill
- Afshin Parsa
- Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
- Anna Köttgen
- Institute of Genetic Epidemiology, Department of Data Driven Medicine, Faculty of Medicine and Medical Center–University of Freiburg
- Pascal Schlosser
- Institute of Genetic Epidemiology, Department of Data Driven Medicine, Faculty of Medicine and Medical Center–University of Freiburg
- Cristian Pattaro
- Eurac Research, Institute for Biomedicine (affiliated with the University of Lübeck)
- DOI
- https://doi.org/10.1038/s41467-024-44709-1
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
