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.

5th Department of Medicine Medical Faculty Mannheim University of Heidelberg Heidelberg Germany

Beijing Institute of Ophthalmology Key Laboratory of Ophthalmology and Visual Sciences Beijing Tongren Hospital Capital Medical University Beijing China

Beijing Tongren Eye Center Beijing Tongren Hospital Capital Medical University Beijing China

BioCore Bioinformatics Core Facility Norwegian University of Science and Technology Trondheim Norway

Biomedical Laboratory Research and Development Tennessee Valley Healthcare System Vanderbilt University Nashville TN USA

Biostatistics Unit Population and Medical Genomics Programme Genomics Research Centre Human Technopole Palazzo Italia Viale Rita Levi‑Montalcini 1 20157 Milan Italy

Cardiovascular Health Research Unit Department of Medicine Department of Epidemiology Department of Health Systems and Population Health University of Washington Seattle WA USA

Cardiovascular Health Research Unit Department of Medicine University of Washington Seattle WA USA

Center for Cardiovascular Prevention Charles University Prague 1st Faculty of Medicine and Thomayer University Hospital Prague Czech Republic

Center for Public Health Genomics University of Virginia Charlottesville Charlottesville VA USA

Centre for Genomic and Experimental Medicine Institute of Genetics and Cancer University of Edinburgh Edinburgh EH4 2XU UK

Centre for Global Health Usher Institute University of Edinburgh Teviot Place Edinburgh EH8 9AG Scotland

Centre for Population Health Research University of Turku and Turku University Hospital Turku Finland

Clinic of Laboratory Medicine St Olavs Hospital Trondheim University Hospital Trondheim Norway

Clinic of Thoracic and Occupational Medicine St Olavs Hospital Trondheim University Hospital Trondheim Norway

Clinical Institute of Medical and Chemical Laboratory Diagnostics Medical University Graz Graz Austria

Department of Anatomy and Cell Biology University Medicine Greifswald Greifswald Germany

Department of Biochemistry Yong Loo Lin School of Medicine National University of Singapore and National University Health System Singapore Singapore

Department of Biomedical Informatics Harvard Medical School Boston MA USA

Department of Biostatistics Gillings School of Global Public Health University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Biostatistics University of Washington Seattle WA USA

Department of Cardiology and Intensive Care Medicine University Hospital OWL of Bielefeld University Campus Klinikum Bielefeld Teutoburger Straße 50 33604 Bielefeld Germany

Department of Cardiology Finnish Cardiovascular Research Center Tampere Faculty of Medicine and Health Technology Tampere University Tampere Finland

Department of Cardiology Heart Center Tampere University Hospital Tampere Finland

Department of Cardiology Södersjukhuset Stockholm Sweden

Department of Clinical and Molecular Medicine Norwegian University of Science and Technology Trondheim Norway

Department of Clinical and Molecular Medicine NTNU Norwegian University of Science and Technology Trondheim Norway

Department of Clinical Biochemistry Landspitali University Hospital Reykjavik Iceland

Department of Clinical Chemistry Fimlab Laboratories and The Wellbeing Services County of Pirkanmaa Tampere Finland

Department of Clinical Chemistry Finnish Cardiovascular Research Center Tampere Faculty of Medicine and Health Technology Tampere University Tampere Finland

Department of Clinical Epidemiology Leiden University Medical Center Leiden the Netherlands

Department of Clinical Physiology and Nuclear Medicine Turku University Hospital Turku Finland

Department of Clinical Physiology Finnish Cardiovascular Research Center Tampere Faculty of Medicine and Health Technology Tampere University Tampere Finland

Department of Clinical Physiology Tampere University Hospital Tampere Finland

Department of Clinical Science and Education Södersjukhuset Karolinska Institutet Stockholm Sweden

Department of Endocrinology St Olavs Hospital Trondheim University Hospital Trondheim Norway

Department of Epidemiology Gillings School of Global Public Health University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD USA

Department of Epidemiology University of Groningen University Medical Center Groningen Groningen the Netherlands

Department of Genetic Epidemiology University of Regensburg Regensburg Germany

Department of Genetics University of North Carolina Chapel Hill NC USA

Department of Genome Informatics Graduate School of Medicine the University of Tokyo Tokyo Japan

Department of Human Genetics and South Texas Diabetes and Obesity Institute University of Texas Rio Grande Valley School of Medicine Brownsville TX USA

Department of Internal Medicine Section of Gerontology and Geriatrics Leiden University Medical Center Leiden the Netherlands

Department of Internal Medicine Section of Nephrology Leiden University Medical Center Leiden the Netherlands

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Solna Sweden

Department of Medicine 2 Charles University Prague 1st Faculty of Medicine Prague Czech Republic

Department of Medicine 4 Nephrology and Primary Care Faculty of Medicine and Medical Center University of Freiburg Freiburg Germany

Department of Medicine University of Illinois at Chicago Chicago IL USA

Department of Medicine University of Leipzig Leipzig Germany

Department of Medicine Yong Loo Lin School of Medicine National University of Singapore and National University Health System Singapore Singapore

Department of Nephrology St Olavs Hospital Trondheim University Hospital Trondheim Norway

Department of Nephrology University Hospital Regensburg Regensburg Germany

Department of Ocular Pathology and Imaging Science Graduate School of Medical Sciences Kyushu University Fukuoka Japan

Department of Ophthalmology Medical Faculty Mannheim University Heidelberg Mannheim Germany

Department of Ophthalmology Yong Loo Lin School of Medicine National University of Singapore and National University Health System Singapore Singapore

Department of Population Medicine and Lifestyle Diseases Prevention Medical University of Bialystok Bialystok Poland

Department of Psychiatry Amsterdam Public Health and Amsterdam Neuroscience Amsterdam UMC Vrije Universiteit and GGZ inGeest Amsterdam the Netherlands

Department of Psychiatry and Psychotherapy University Medicine Greifswald Greifswald Germany

Department of Psychology University of Miami Coral Gables FL USA

Department of Public Health and Primary Care Leiden University Medical Center Leiden the Netherlands

Department of Public Health Sciences Loyola University Chicago Maywood IL USA

Department of Social Medicine Population and Public Health University of California at Riverside School of Medicine Riverside CA USA

Department of Statistical Genetics Osaka University Graduate School of Medicine Osaka Japan

Department of Veteran's Affairs Tennessee Valley Healthcare System Vanderbilt University Nashville TN USA

Division of Biomedical Informatics and Personalized Medicine School of Medicine University of Colorado Denver Anschutz Medical Campus Aurora CO USA

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Epidemiology Department of Medicine Vanderbilt Genetics Institute Vanderbilt University Medical Center Nashville TN USA

Division of Kidney Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda MD USA

Division of Medicine and Laboratory Sciences Faculty of Medicine University of Oslo Oslo Norway

Division of Nephrology and Hypertension Department of Medicine University of Utah Salt Lake City UT USA

Division of Nephrology and Hypertension Loyola University Chicago Chicago IL USA

Division of Nephrology Department of Medicine University of Mississippi Medical Center Jackson MS USA

Division of Nephrology University of Washington Seattle WA USA

Division of Preventive Medicine Brigham and Women's Hospital Boston MA USA

Division of Quantitative Sciences Department of Obstetrics and Gynecology Vanderbilt Genetics Institute Vanderbilt Epidemiology Center Institute for Medicine and Public Health Vanderbilt University Medical Center Nashville TN USA

Division of Statistical Genomics Department of Genetics Washington University School of Medicine St Louis MO USA

Duke NUS Medical School Singapore Singapore

DZHK partner site Greifswald Greifswald Germany

eCODE Genetics Amgen Inc Reykjavik Iceland

Einthoven Laboratory of Experimental Vascular Research Leiden University Medical Center Leiden the Netherlands

Eurac Research Institute for Biomedicine Bolzano Italy

Faculty of Medicine School of Health Sciences University of Iceland Reykjavik Iceland

Finnish Institute for Health and Welfare Helsinki Finland

Finnish Medicines Agency Kuopio Finland

Genetics Merck and Co Inc Kenilworth NJ USA

Genome Institute of Singapore Agency for Science Technology and Research Singapore Singapore

Harvard Medical School Boston MA USA

Helmholtz Institute for Metabolic Obesity and Vascular Research of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig Leipzig Germany

Iceland School of Engineering and Natural Sciences University of Iceland Reykjavik Iceland

Institute for Community Medicine University Medicine Greifswald Greifswald Germany

Institute for Laboratory Medicine University of Leipzig Leipzig Germany

Institute for Maternal and Child Health IRCCS 'Burlo Garofolo' Trieste Italy

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Leipzig Germany

Institute for Minority Health Research University of Illinois at Chicago Chicago IL USA

Institute of Clinical Chemistry and Laboratory Medicine University Hospital Regensburg Regensburg Germany

Institute of Clinical Chemistry and Laboratory Medicine University Medicine Greifswald Greifswald Germany

Institute of Genetic Epidemiology Department of Data Driven Medicine Faculty of Medicine and Medical Center University of Freiburg Freiburg Germany

Institute of Genetics and Biophysics 'Adriano Buzzati Traverso' CNR Naples Italy

Institute of Molecular and Clinical Ophthalmology Basel Switzerland

Interdisciplinary Centre Psychopathology and Emotion regulation Department of Psychiatry University of Groningen University Medical Center Groningen Groningen the Netherlands

Interfaculty Institute for Genetics and Functional Genomics University Medicine Greifswald Greifswald Germany

Janssen Pharmaceuticals Inc Titusville NJ 08560 USA

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

Kidney Research Institute University of Washington Seattle WA USA

Laboratory for Statistical Analysis RIKEN Center for Integrative Medical Sciences Yokohama Japan

Laboratory for Systems Genetics RIKEN Center for Integrative Medical Sciences Yokohama Japan

Laboratory of Clinical Genome Sequencing Graduate School of Frontier Sciences The University of Tokyo Tokyo Japan

Laboratory of Complex Trait Genomics Department of Computational Biology and Medical Sciences Graduate School of Frontier Sciences The University of Tokyo Tokyo Japan

LIFE Research Center for Civilization Diseases University of Leipzig Leipzig Germany

Massachusetts Veterans Epidemiology Research and Information Center VA Cooperative Studies Program VA Boston Healthcare System Boston MA USA

Medical Research Council Human Genetics Unit Institute of Genetics and Cancer University of Edinburgh Edinburgh EH4 2XU UK

Medpharmgene Montreal QC Canada

Memory Impairment and Neurodegenerative Dementia Center University of Mississippi Medical Center Jackson MS USA

Montreal University Hospital Research Center CHUM Montréal QC Canada

MRC Integrative Epidemiology Unit Population Health Sciences Bristol Medical School University of Bristol Bristol UK

Network Aging Research Heidelberg University Heidelberg Germany

Ophthalmology and Visual Sciences Academic Clinical Program Duke NUS Medical School Singapore Singapore

Privatpraxis Prof Jonas und Dr Panda Jonas Heidelberg Germany

Program in Medical and Population Genetics Broad Institute of Harvard and MIT Cambridge MA USA

QIMR Berghofer Medical Research Institute Brisbane QLD Australia

Research Center of Applied and Preventive Cardiovascular Medicine University of Turku Turku Finland

Research Program for Clinical and Molecular Metabolism Faculty of Medicine University of Helsinki Helsinki Finland

Saw Swee Hock School of Public Health National University of Singapore and National University Health System Singapore Singapore

School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China

Singapore Eye Research Institute Singapore National Eye Center Singapore Singapore

Synlab Academy Synlab Holding Deutschland GmbH Augsburg Germany

SYNLAB MVZ Humangenetik Mannheim Mannheim Germany

Tampere Centre for Skills Training and Simulation Faculty of Medicine and Health Technology Tampere University Tampere Finland

The George Institute for Global Health School of Public Health Imperial College London London UK

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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

Tsinghua Medicine Tsinghua University Beijing China

University Hospital for Children and Adolescents Pediatric Research Unit Medical Faculty University Medical Center University of Leipzig Leipzig Germany

University of Queensland Brisbane QLD Australia

University of Split Medical School Split Croatia

Usher Institute University of Edinburgh Teviot Place Edinburgh EH8 9AG Scotland

Vanderbilt Genetics Institute Vanderbilt University Medical Center Nashville TN USA

Vanderbilt University Medical Center Division of Nephrology and Hypertension Nashville TN USA

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