BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Biometric Psychiatric Genetics Research Unit Alexandru Obregia Clinical Psychiatric Hospital Bucharest Romania

Broad Institute of MIT and Harvard Cambridge Massachusetts; Institute of Genomics University of Tartu Tartu Estonia

Cancer Epidemiology and Prevention M Sklodowska Curie National Research Institute of Oncology Warsaw Poland

Center for Psychopharmacology Diakonhjemmet Hospital Oslo Norway; Department of Pharmaceutical Biosciences School of Pharmacy University of Oslo Oslo Norway

Center for Statistical Genetics and Department of Biostatistics University of Michigan Ann Arbor Michigan

Centre for Addiction and Mental Health Toronto Ontario Canada

Centre for Affective Disorders Institute of Psychiatry Psychology and Neuroscience London United Kingdom; Department of Psychiatry and Addiction Medicine Assistance Publique Hôpitaux de Paris Paris France; UMR S1144 Team 1 Biomarkers of relapse and therapeutic response in addiction and mood disorders INSERM Paris France; Psychiatry Université Paris Diderot Paris France

Centre for Human Genetics University of Marburg Marburg Germany; Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Bonn Germany

Centre for Integrative Sequencing Copenhagen Denmark

Child and Adolescent Psychiatry Erasmus Medical Center Rotterdam the Netherlands

Department of Biological Psychology Netherlands Twin Register Vrije Universiteit Amsterdam Amsterdam the Netherlands; Amsterdam Public Health Research Institute Amsterdam UMC Amsterdam the Netherlands

Department of Biomedicine Aarhus University Aarhus Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research Aarhus Denmark

Department of Biomedicine Aarhus University Aarhus Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research Copenhagen Denmark; Center for Genome Analysis and Personalized Medicine Aarhus Denmark

Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark; Institute of Biological Psychiatry Mental Health Center Sct Hans Mental Health Services Copenhagen Roskilde Denmark

Department of Clinical Neuroscience Max Planck Institute of Experimental Medicine Göttingen Germany

Department of Clinical Neuroscience Psychiatry Section Karolinska Institutet Stockholm Sweden; Norwegian Centre for Mental Disorders Research KG Jebsen Centre for Psychosis Research Institute of Clinical Medicine University of Oslo Oslo Norway

Department of Clinical Sciences Psychiatry Umeå University Medical Faculty Umeå Sweden

Department of Environmental Epidemiology Nofer Institute of Occupational Medicine Lodz Poland

Department of Genetic Epidemiology in Psychiatry Central Institute of Mental Health Medical Faculty Mannheim Heidelberg University Mannheim Germany

Department of Health Sciences Research Mayo Clinic Rochester Minnesota

Department of Medical and Molecular Genetics King's College London London United Kingdom

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden; Institute of Neuroscience and Physiology the Sahlgrenska Academy at Gothenburg University Gothenburg Sweden

Department of Medical Genetics Oslo University Hospital Oslo Norway; NORMENT Centre Department of Clinical Science University of Bergen Bergen Norway

Department of Mental Health Norwegian University of Science and Technology NTNU Trondheim Norway; Department of Psychiatry St Olavs' University Hospital Trondheim Norway

Department of Psychiatry and Addiction Medicine Assistance Publique Hôpitaux de Paris Paris France; UMR S1144 Team 1 Biomarkers of relapse and therapeutic response in addiction and mood disorders INSERM Paris France; Psychiatry Université Paris Diderot Paris France; Paris Bipolar and TRD Expert Centres FondaMental Foundation Paris France

Department of Psychiatry and Behavioral Neuroscience University of Chicago Chicago Illinois; Department of Psychiatry and Behavioral Sciences North Shore University Health System Evanston Illinois

Department of Psychiatry and Behavioral Sciences SUNY Upstate Medical University Syracuse New York; Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine Baltimore Maryland; Institute of Psychiatric Phenomics and Genomics University Hospital LMU Munich Munich Germany; Department of Genetic Epidemiology in Psychiatry Central Institute of Mental Health Medical Faculty Mannheim Heidelberg University Mannheim Germany; Department of Psychiatry and Psychotherapy University Medical Center Göttingen Göttingen Germany

Department of Psychiatry and Neuropsychology School for Mental Health and Neuroscience Faculty of Health Medicine and Life Sciences Maastricht University Maastricht the Netherlands; Psychiatric and Neurodevelopmental Genetics Unit Department of Psychiatry and Center for Genomic Medicine Massachusetts General Hospital Boston Massachusetts; Department of Psychiatry Harvard Medical School Boston Massachusetts; Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts

Department of Psychiatry and Psychology Mayo Clinic Rochester Minnesota

Department of Psychiatry and Psychotherapy University Medicine Greifswald Greifswald Germany

Department of Psychiatry Columbia University College of Physicians and Surgeons New York New York; Division of Translational Epidemiology New York State Psychiatric Institute New York New York

Department of Psychiatry Dalhousie University Halifax Nova Scotia Canada

Department of Psychiatry Dalhousie University Halifax Nova Scotia Canada; National Institute of Mental Health Klecany Czech Republic

Department of Psychiatry Fujita Health University School of Medicine Toyoake Aichi Japan

Department of Psychiatry Icahn School of Medicine at Mount Sinai New York New York; Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York New York; Social Genetic and Developmental Psychiatry Centre King's College London London United Kingdom

Department of Psychiatry Laboratory of Psychiatric Genetics Poznan University of Medical Sciences Poznan Poland

Department of Psychiatry Lausanne University Hospital and University of Lausanne Lausanne Switzerland

Department of Psychiatry Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China; State Key Laboratory for Brain and Cognitive Sciences Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China; Centre for Genomic Sciences The University of Hong Kong Hong Kong SAR China

Department of Psychiatry Melbourne Medical School University of Melbourne Melbourne Victoria Australia; Florey Institute for Neuroscience and Mental Health University of Melbourne Parkville Victoria Australia; Department of Psychiatry University of Münster Münster Germany

Department of Psychiatry Mood Disorders Program McGill University Health Center Montréal Québec Canada

Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt Frankfurt am Main Germany

Department of Psychiatry University of California San Diego La Jolla California

Department of Psychiatry University of Halle Halle Germany

Department of Psychiatry University of Halle Halle Germany; Department of Psychiatry University of Munich Munich Germany

Department of Psychiatry University of Iowa Iowa City Iowa

Department of Psychiatry Vrije Universiteit Medical Center and GGZ inGeest Amsterdam the Netherlands

Department of Translational Research in Psychiatry Max Planck Institute of Psychiatry Munich Germany; Max Planck Institute of Psychiatry Munich Germany

Departments of Genetics and Psychiatry University of North Carolina at Chapel Hill Chapel Hill North Carolina; Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Departments of Human Genetics and Neuroscience Icahn School of Medicine at Mount Sinai New York New York; Department of Psychiatry Icahn School of Medicine at Mount Sinai New York New York; Friedman Brain Institute Icahn School of Medicine at Mount Sinai New York New York

Discipline of Psychiatry The University of Adelaide Adelaide South Austrlalia Australia

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda Maryland

Division of Psychiatry University of Edinburgh Edinburgh United Kingdom

Division of Psychiatry University of Edinburgh Edinburgh United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology University of Edinburgh Edinburgh United Kingdom

Faculté de Médecine Université Paris Est Créteil France; Department of Psychiatry and Addiction Medicine Assistance Publique Hôpitaux de Paris Paris France; Institut national de la santé et de la recherche médicale Paris France

Faculté de Médecine Université Paris Est Créteil France; INSERM U955 Psychiatrie Translationnelle Créteil France

Innovation Center on Sex Differences in Medicine Massachusetts General Hospital Boston Massachusetts; Department of Biomedical Sciences Colorado State University Fort Collins Colorado

Innovation Center on Sex Differences in Medicine Massachusetts General Hospital Boston Massachusetts; Department of Psychiatry and Vincent Department of Obstetrics Gynecology and Reproductive Biology Massachusetts General Hospital Boston Massachusetts; MGH MIT HMS Athinoula A Martinos Center for Biomedical Imaging Charlestown Massachusetts; Departments of Psychiatry and Medicine Harvard Medical School Boston Massachusetts

Institute for Genomic Health SUNY Downstate Medical Center College of Medicine Brooklyn New York; Department of Psychiatry and Zilkha Neurogenetics Institute Keck School of Medicine at University of Southern California Los Angeles California

Institute of Community Medicine University Medicine Greifswald Greifswald Germany

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Bonn Germany

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Bonn Germany; Department of Child and Adolescent Psychiatry Psychosomatics and Psychotherapy University Hospital Essen University of Duisburg Essen Duisburg Germany

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Bonn Germany; Institute of Neuroscience and Medicine Research Centre Jülich Jülich Germany; Department of Biomedicine University of Basel Basel Switzerland; Institute of Medical Genetics and Pathology University Hospital Basel Basel Switzerland

Institute of Psychiatric Phenomics and Genomics Munich Germany

Institute of Psychiatric Phenomics and Genomics University Hospital LMU Munich Munich Germany

Institute of Psychiatry King's College London London United Kingdom

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

ISGlobal Barcelona Spain

Kaiser Permanente Northern California San Francisco California

Lieber Institute for Brain Development Baltimore Maryland; Departments of Psychiatry Neurology Neuroscience and Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore Maryland

Medical and Population Genetics Broad Institute of MIT and Harvard Cambridge Massachusetts; Department of Psychiatry Icahn School of Medicine at Mount Sinai New York New York; Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York New York

Mental Health Department University Regional Hospital Biomedical Research Institute of Málaga Málaga Spain

Mental Health Neuroscience Research Department Division of Psychiatry Faculty of Brain Sciences University College London London United Kingdom

Molecular Psychiatry Laboratory Division of Psychiatry University College London London United Kingdom

MRC Centre for Neuropsychiatric Genetics and Genomics Institute of Psychological Medicine and Clinical Neurosciences School of Medicine Cardiff University Cardiff United Kingdom

Neuropsychiatric Genetics Research Group Department of Psychiatry Trinity College Dublin Dublin Ireland

Neuroscience Research Australia Sydney New South Wales Australia; School of Medical Sciences University of New South Wales Sydney New South Wales Australia

NIHR Maudsley Biomedical Research Centre King's College London London United Kingdom

Norwegian Centre for Mental Disorders Research Institute of Clinical Medicine University of Oslo and Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

Priority Centre for Translational Neuroscience and Mental Health University of Newcastle Newcastle New South Wales Australia

Psychiatric and Neurodevelopmental Genetics Unit Department of Psychiatry and Center for Genomic Medicine Massachusetts General Hospital Boston Massachusetts; Biogen Inc Cambridge Massachusetts

Psychiatric and Neurodevelopmental Genetics Unit Department of Psychiatry and Center for Genomic Medicine Massachusetts General Hospital Boston Massachusetts; Department of Psychiatry Harvard Medical School Boston Massachusetts; Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts

Psychiatric and Neurodevelopmental Genetics Unit Department of Psychiatry and Center for Genomic Medicine Massachusetts General Hospital Boston Massachusetts; Department of Psychiatry Harvard Medical School Boston Massachusetts; Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts; Concert Pharmaceuticals Inc Lexington Massachusetts

Psychiatric and Neurodevelopmental Genetics Unit Department of Psychiatry and Center for Genomic Medicine Massachusetts General Hospital Boston Massachusetts; Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts; Institute for Molecular Medicine Finland University of Helsinki Helsinki Finland

Psychiatry and Behavioral Sciences Stanford University Stanford California

Psychiatry and The Behavioral Sciences University of Southern California Los Angeles California

Queensland Brain Institute University of Queensland Brisbane Queensland Australia; Queensland Centre for Mental Health Research The Park Centre for Mental Health Wacol Queensland Australia

Queensland Brain Institute University of Queensland Brisbane Queensland Australia; Queensland Centre for Mental Health Research University of Queensland Brisbane Queensland Australia

Research Division and Department of General Psychiatry Institute of Mental Health Singapore Singapore; Duke National University of Singapore Graduate Medical School Singapore

Research Institute Lindner Center of HOPE Mason Ohio

Schizophrenia Research Institute Sydney New South Wales Australia; School of Biomedical Sciences and Pharmacy University of Newcastle Callaghan New South Wales Australia; Priority Centre for Translational Neuroscience and Mental Health University of Newcastle Newcastle New South Wales Australia

School of Biomedical Sciences and Pharmacy University of Newcastle Callaghan New South Wales Australia; Priority Centre for Translational Neuroscience and Mental Health University of Newcastle Newcastle New South Wales Australia; Schizophrenia Research Institute Sydney New South Wales Australia

School of Biomedical Sciences and Pharmacy University of Newcastle Callaghan New South Wales Australia; Schizophrenia Research Institute Sydney New South Wales Australia

School of Psychiatry University of New South Wales Sydney New South Wales Australia

School of Psychology and Counseling Queensland University of Technology Brisbane Queensland Australia

School of Psychology University of Queensland Brisbane Queensland Australia; Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia

Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts; Broad Institute of MIT and Harvard Cambridge Massachusetts; Medical and Population Genetics Broad Institute of MIT and Harvard Cambridge Massachusetts; Institute of Genomics University of Tartu Tartu Estonia

Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts; Departments of Neurology and Genetics Yale School of Medicine New Haven Connecticut

The Feinstein Institute for Medical Research Manhasset New York; The Zucker School of Medicine at Hofstra Northwell Hempstead New York; The Zucker Hillside Hospital Glen Oaks New York

The Lundbeck Foundation Initiative for Integrative Psychiatric Research Copenhagen Denmark; Center for Neonatal Screening Department for Congenital Disorders Statens Serum Institut Copenhagen Denmark

The Lundbeck Foundation Initiative for Integrative Psychiatric Research Copenhagen Denmark; Copenhagen Mental Health Center Mental Health Services Capital Region of Denmark Copenhagen Copenhagen Denmark; Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

The Lundbeck Foundation Initiative for Integrative Psychiatric Research Copenhagen Denmark; Psychosis Research Unit Aarhus University Hospital Risskov Denmark

University Medical Center Utrecht Department of Psychiatry Rudolf Magnus Institute of Neuroscience Utrecht the Netherlands; Department of Human Genetics University of California Los Angeles California; David Geffen School of Medicine and Center for Neurobehavioral Genetics Semel Institute for Neuroscience and Human Behavior University of California Los Angeles California

University of Aberdeen Institute of Medical Sciences Aberdeen United Kingdom

University of Liverpool Liverpool United Kingdom; Department of Translational Research in Psychiatry Max Planck Institute of Psychiatry Munich Germany; Munich Cluster for Systems Neurology Munich Germany

Virginia Institute for Psychiatric and Behavioral Genetics Departments of Psychiatry and Human and Molecular Genetics Virginia Commonwealth University Richmond Virginia

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