Gabriëlla A M Blokland1, Jakob Grove2, Chia-Yen Chen3, Chris Cotsapas4, Stuart Tobet5, Robert Handa5, David St Clair6, Todd Lencz7, Bryan J Mowry8, Sathish Periyasamy9, Murray J Cairns10, Paul A Tooney11, Jing Qin Wu12, Brian Kelly13, George Kirov14, Patrick F Sullivan15, Aiden Corvin16, Brien P Riley17, Tõnu Esko18, Lili Milani19, Erik G Jönsson20, Aarno Palotie21, Hannelore Ehrenreich22, Martin Begemann22, Agnes Steixner-Kumar22, Pak C Sham23, Nakao Iwata24, Daniel R Weinberger25, Pablo V Gejman26, Alan R Sanders26, Joseph D Buxbaum27, Dan Rujescu28, Ina Giegling28, Bettina Konte29, Annette M Hartmann29, Elvira Bramon30, Robin M Murray31, Michele T Pato32, Jimmy Lee33, Ingrid Melle34, Espen Molden35, Roel A Ophoff36, Andrew McQuillin37, Nicholas J Bass37, Rolf Adolfsson38, Anil K Malhotra7, Nicholas G Martin39, Janice M Fullerton40, Philip B Mitchell41, Peter R Schofield40, Andreas J Forstner42, Franziska Degenhardt43, Sabrina Schaupp44, Ashley L Comes45, Manolis Kogevinas46, José Guzman-Parra47, Andreas Reif48, Fabian Streit49, Lea Sirignano49, Sven Cichon50, Maria Grigoroiu-Serbanescu51, Joanna Hauser52, Jolanta Lissowska53, Fermin Mayoral47, Bertram Müller-Myhsok54, Beata Świątkowska55, Thomas G Schulze56, Markus M Nöthen57, Marcella Rietschel49, John Kelsoe58, Marion Leboyer59, Stéphane Jamain60, Bruno Etain61, Frank Bellivier62, John B Vincent63, Martin Alda64, Claire O'Donovan65, Pablo Cervantes66, Joanna M Biernacka67, Mark Frye68, Susan L McElroy69, Laura J Scott70, Eli A Stahl71, Mikael Landén72, Marian L Hamshere14, Olav B Smeland34, Srdjan Djurovic73, Arne E Vaaler74, Ole A Andreassen34, Bernhard T Baune75, Tracy Air76, Martin Preisig77, Rudolf Uher65, Douglas F Levinson78, Myrna M Weissman79, James B Potash80, Jianxin Shi81, James A Knowles82, Roy H Perlis83, Susanne Lucae84, Dorret I Boomsma85, Brenda W J H Penninx86, Jouke-Jan Hottenga85, Eco J C de Geus85, Gonneke Willemsen85, Yuri Milaneschi86, Henning Tiemeier87, Hans J Grabe88, Alexander Teumer89, Sandra Van der Auwera88, Uwe Völker90, Steven P Hamilton91, Patrik K E Magnusson92, Alexander Viktorin92, Divya Mehta93, Niamh Mullins94, Mark J Adams95, Gerome Breen96, Andrew M McIntosh97, Cathryn M Lewis98, David M Hougaard99, Merete Nordentoft100, Ole Mors101, Preben B Mortensen102, Thomas Werge103, Thomas D Als104, Anders D Børglum104, Tracey L Petryshen105, Jordan W Smoller83, Jill M Goldstein106. 1. 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. Electronic address: gam.blokland@maastrichtuniversity.nl. 2. Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark; Center for Genome Analysis and Personalized Medicine, Aarhus, Denmark; Bioinformatics Research Centre (BiRC), Aarhus, Denmark. 3. Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts; Biogen Inc., Cambridge, Massachusetts. 4. 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. 5. Innovation Center on Sex Differences in Medicine (ICON), Massachusetts General Hospital, Boston, Massachusetts; Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado. 6. University of Aberdeen, Institute of Medical Sciences, Aberdeen, United Kingdom. 7. 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. 8. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia; Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia. 9. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia; Queensland Centre for Mental Health Research, The Park - Centre for Mental Health, Wacol, Queensland, Australia. 10. 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. 11. 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. 12. School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia; Schizophrenia Research Institute, Sydney, New South Wales, Australia. 13. Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, New South Wales, Australia. 14. MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. 15. 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. 16. Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland. 17. Virginia Institute for Psychiatric and Behavioral Genetics, Departments of Psychiatry and Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia. 18. 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. 19. Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Institute of Genomics, University of Tartu, Tartu, Estonia. 20. Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden; Norwegian Centre for Mental Disorders Research (NORMENT), KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 21. 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 (FIMM), University of Helsinki, Helsinki, Finland. 22. Department of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany. 23. 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. 24. Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan. 25. 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. 26. Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois. 27. 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. 28. Department of Psychiatry, University of Halle, Halle, Germany; Department of Psychiatry, University of Munich, Munich, Germany. 29. Department of Psychiatry, University of Halle, Halle, Germany. 30. Mental Health Neuroscience Research Department, Division of Psychiatry, Faculty of Brain Sciences, University College London, London, United Kingdom. 31. Institute of Psychiatry, King's College London, London, United Kingdom. 32. 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. 33. Research Division and Department of General Psychiatry, Institute of Mental Health, Singapore, Singapore; Duke-National University of Singapore Graduate Medical School, Singapore. 34. Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. 35. Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway; Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway. 36. 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. 37. Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, United Kingdom. 38. Department of Clinical Sciences, Psychiatry, Umeå University Medical Faculty, Umeå, Sweden. 39. School of Psychology, University of Queensland, Brisbane, Queensland, Australia; Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. 40. Neuroscience Research Australia, Sydney, New South Wales, Australia; School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia. 41. School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia. 42. Centre for Human Genetics, University of Marburg, Marburg, Germany; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany. 43. Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Duisburg, Germany. 44. Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany. 45. Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany; International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany. 46. ISGlobal, Barcelona, Spain. 47. Mental Health Department, University Regional Hospital, Biomedical Research Institute of Málaga (IBIMA), Málaga, Spain. 48. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany. 49. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 50. Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany; Department of Biomedicine, University of Basel, Basel, Switzerland; Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland. 51. Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania. 52. Department of Psychiatry, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, Poland. 53. Cancer Epidemiology and Prevention, M. Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. 54. University of Liverpool, Liverpool, United Kingdom; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 55. Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland. 56. 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 (IPPG), 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. 57. Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany. 58. Department of Psychiatry, University of California San Diego, La Jolla, California. 59. 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 (INSERM), Paris, France. 60. Faculté de Médecine, Université Paris Est, Créteil, France; INSERM U955, Psychiatrie Translationnelle, Créteil, France. 61. 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. 62. 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. 63. Centre for Addiction and Mental Health, Toronto, Ontario, Canada. 64. Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada; National Institute of Mental Health, Klecany, Czech Republic. 65. Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada. 66. Department of Psychiatry, Mood Disorders Program, McGill University Health Center, Montréal, Québec, Canada. 67. Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. 68. Department of Psychiatry & Psychology, Mayo Clinic, Rochester, Minnesota. 69. Research Institute, Lindner Center of HOPE, Mason, Ohio. 70. Center for Statistical Genetics and Department of Biostatistics, University of Michigan, Ann Arbor, Michigan. 71. 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. 72. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Institute of Neuroscience and Physiology, the Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden. 73. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; NORMENT Centre, Department of Clinical Science, University of Bergen, Bergen, Norway. 74. Department of Mental Health, Norwegian University of Science and Technology - NTNU, Trondheim, Norway; Department of Psychiatry, St Olavs' University Hospital, Trondheim, Norway. 75. 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. 76. Discipline of Psychiatry, The University of Adelaide, Adelaide, South Austrlalia, Australia. 77. Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. 78. Psychiatry & Behavioral Sciences, Stanford University, Stanford, California. 79. 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. 80. Department of Psychiatry, University of Iowa, Iowa City, Iowa. 81. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. 82. Psychiatry & The Behavioral Sciences, University of Southern California, Los Angeles, California. 83. 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. 84. Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany; Max Planck Institute of Psychiatry, Munich, Germany. 85. Department of Biological Psychology/Netherlands Twin Register, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Amsterdam Public Health Research Institute, Amsterdam UMC, Amsterdam, the Netherlands. 86. Department of Psychiatry, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, the Netherlands. 87. Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, the Netherlands. 88. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany. 89. Institute of Community Medicine, University Medicine Greifswald, Greifswald, Germany. 90. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany. 91. Kaiser Permanente Northern California, San Francisco, California. 92. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 93. School of Psychology and Counseling, Queensland University of Technology, Brisbane, Queensland, Australia. 94. 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. 95. Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom. 96. NIHR Maudsley Biomedical Research Centre, King's College London, London, United Kingdom. 97. Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom. 98. Department of Medical & Molecular Genetics, King's College London, London, United Kingdom. 99. The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark. 100. The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), 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. 101. The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark; Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark. 102. Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark; National Centre for Register-Based Research (NCCR), Aarhus University, Aarhus, Denmark; Centre for Integrated Register-based Research (CIRRAU), Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark. 103. 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. 104. Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark; Center for Genome Analysis and Personalized Medicine, Aarhus, Denmark. 105. 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. 106. Innovation Center on Sex Differences in Medicine (ICON), Massachusetts General Hospital, Boston, Massachusetts; Department of Psychiatry and Vincent Department of Obstetrics, Gynecology & 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. Electronic address: jill_goldstein@hms.harvard.edu.
Abstract
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.
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.
Authors: Krista M Hennig; Daniel M Fass; Wen-Ning Zhao; Steven D Sheridan; Ting Fu; Serkan Erdin; Alexei Stortchevoi; Diane Lucente; Jannine D Cody; David Sweetser; James F Gusella; Michael E Talkowski; Stephen J Haggarty Journal: Mol Neuropsychiatry Date: 2017-07-14
Authors: Jeanne E Savage; Philip R Jansen; Sven Stringer; Kyoko Watanabe; Julien Bryois; Christiaan A de Leeuw; Mats Nagel; Swapnil Awasthi; Peter B Barr; Jonathan R I Coleman; Katrina L Grasby; Anke R Hammerschlag; Jakob A Kaminski; Robert Karlsson; Eva Krapohl; Max Lam; Marianne Nygaard; Chandra A Reynolds; Joey W Trampush; Hannah Young; Delilah Zabaneh; Sara Hägg; Narelle K Hansell; Ida K Karlsson; Sten Linnarsson; Grant W Montgomery; Ana B Muñoz-Manchado; Erin B Quinlan; Gunter Schumann; Nathan G Skene; Bradley T Webb; Tonya White; Dan E Arking; Dimitrios Avramopoulos; Robert M Bilder; Panos Bitsios; Katherine E Burdick; Tyrone D Cannon; Ornit Chiba-Falek; Andrea Christoforou; Elizabeth T Cirulli; Eliza Congdon; Aiden Corvin; Gail Davies; Ian J Deary; Pamela DeRosse; Dwight Dickinson; Srdjan Djurovic; Gary Donohoe; Emily Drabant Conley; Johan G Eriksson; Thomas Espeseth; Nelson A Freimer; Stella Giakoumaki; Ina Giegling; Michael Gill; David C Glahn; Ahmad R Hariri; Alex Hatzimanolis; Matthew C Keller; Emma Knowles; Deborah Koltai; Bettina Konte; Jari Lahti; Stephanie Le Hellard; Todd Lencz; David C Liewald; Edythe London; Astri J Lundervold; Anil K Malhotra; Ingrid Melle; Derek Morris; Anna C Need; William Ollier; Aarno Palotie; Antony Payton; Neil Pendleton; Russell A Poldrack; Katri Räikkönen; Ivar Reinvang; Panos Roussos; Dan Rujescu; Fred W Sabb; Matthew A Scult; Olav B Smeland; Nikolaos Smyrnis; John M Starr; Vidar M Steen; Nikos C Stefanis; Richard E Straub; Kjetil Sundet; Henning Tiemeier; Aristotle N Voineskos; Daniel R Weinberger; Elisabeth Widen; Jin Yu; Goncalo Abecasis; Ole A Andreassen; Gerome Breen; Lene Christiansen; Birgit Debrabant; Danielle M Dick; Andreas Heinz; Jens Hjerling-Leffler; M Arfan Ikram; Kenneth S Kendler; Nicholas G Martin; Sarah E Medland; Nancy L Pedersen; Robert Plomin; Tinca J C Polderman; Stephan Ripke; Sophie van der Sluis; Patrick F Sullivan; Scott I Vrieze; Margaret J Wright; Danielle Posthuma Journal: Nat Genet Date: 2018-06-25 Impact factor: 38.330
Authors: Marianne L Seney; Zhiguang Huo; Kelly Cahill; Leon French; Rachel Puralewski; Joyce Zhang; Ryan W Logan; George Tseng; David A Lewis; Etienne Sibille Journal: Biol Psychiatry Date: 2018-02-19 Impact factor: 13.382
Authors: Taru Tukiainen; Alexandra-Chloé Villani; Angela Yen; Manuel A Rivas; Jamie L Marshall; Rahul Satija; Matt Aguirre; Laura Gauthier; Mark Fleharty; Andrew Kirby; Beryl B Cummings; Stephane E Castel; Konrad J Karczewski; François Aguet; Andrea Byrnes; Tuuli Lappalainen; Aviv Regev; Kristin G Ardlie; Nir Hacohen; Daniel G MacArthur Journal: Nature Date: 2017-10-11 Impact factor: 49.962
Authors: Emily R Mahoney; Logan Dumitrescu; Annah M Moore; Francis E Cambronero; Philip L De Jager; Mary Ellen I Koran; Vladislav A Petyuk; Renã A S Robinson; Sandeep Goyal; Julie A Schneider; David A Bennett; Angela L Jefferson; Timothy J Hohman Journal: Mol Psychiatry Date: 2019-07-22 Impact factor: 15.992
Authors: Christian Benner; Chris C A Spencer; Aki S Havulinna; Veikko Salomaa; Samuli Ripatti; Matti Pirinen Journal: Bioinformatics Date: 2016-01-14 Impact factor: 6.937
Authors: Gabriel E Hoffman; Yixuan Ma; Kelsey S Montgomery; Jaroslav Bendl; Manoj Kumar Jaiswal; Alex Kozlenkov; Mette A Peters; Stella Dracheva; John F Fullard; Andrew Chess; Bernie Devlin; Solveig K Sieberts; Panos Roussos Journal: Biol Psychiatry Date: 2021-03-25 Impact factor: 13.382
Authors: Jennifer L Kruse; Richard Olmstead; Gerhard Hellemann; Elizabeth C Breen; Susannah J Tye; John O Brooks; Benjamin Wade; Eliza Congdon; Randall Espinoza; Katherine L Narr; Michael R Irwin Journal: J Psychiatr Res Date: 2021-06-09 Impact factor: 5.250
Authors: Joanna Martin; Kimiya Asjadi; Leon Hubbard; Kimberley Kendall; Antonio F Pardiñas; Bradley Jermy; Cathryn M Lewis; Bernhard T Baune; Dorret I Boomsma; Steven P Hamilton; Susanne Lucae; Patrik K Magnusson; Nicholas G Martin; Andrew M McIntosh; Divya Mehta; Ole Mors; Niamh Mullins; Brenda W J H Penninx; Martin Preisig; Marcella Rietschel; Ian Jones; James T R Walters; Frances Rice; Anita Thapar; Michael O'Donovan Journal: PLoS One Date: 2021-09-02 Impact factor: 3.240