Sex-stratified genome-wide association meta-analysis of major depressive disorder

Jodi T. Thomas (), Jackson G. Thorp, Floris Huider, Poppy Z. Grimes, Rujia Wang, Pierre Youssef, Jonathan R. I. Coleman, Enda M. Byrne, Mark Adams, Sarah E. Medland, Ian B. Hickie, Catherine M. Olsen, David C. Whiteman, Heather C. Whalley, Brenda W.J.H. Penninx, Hanna M. van Loo, Eske M. Derks, Thalia C. Eley, Gerome Breen, Dorret I. Boomsma, Naomi R. Wray, Nicholas G. Martin and Brittany L. Mitchell ()
Additional contact information
Jodi T. Thomas: QIMR Berghofer Medical Research Institute, Brain and Mental Health Program
Jackson G. Thorp: QIMR Berghofer Medical Research Institute, Brain and Mental Health Program
Floris Huider: Vrije Universiteit Amsterdam, Department of Biological Psychology, Faculty of Behavioral and Movement Sciences
Poppy Z. Grimes: University of Edinburgh, Division of Psychiatry, Centre for Clinical Brain Sciences
Rujia Wang: King’s College London, Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience
Pierre Youssef: QIMR Berghofer Medical Research Institute, Brain and Mental Health Program
Jonathan R. I. Coleman: King’s College London, Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience
Enda M. Byrne: Child Health Research Centre, University of Queensland
Mark Adams: University of Edinburgh, Division of Psychiatry, Centre for Clinical Brain Sciences
Sarah E. Medland: QIMR Berghofer Medical Research Institute, Brain and Mental Health Program
Ian B. Hickie: University of Sydney, Brain and Mind Centre, Faculty of Medicine and Health
Catherine M. Olsen: QIMR Berghofer Medical Research Institute, Population Health Program
David C. Whiteman: QIMR Berghofer Medical Research Institute, Population Health Program
Heather C. Whalley: University of Edinburgh, Division of Psychiatry, Centre for Clinical Brain Sciences
Brenda W.J.H. Penninx: Amsterdam Public Health Research Institute
Hanna M. van Loo: University Medical Center Groningen, Department of Psychiatry, University of Groningen
Eske M. Derks: QIMR Berghofer Medical Research Institute, Brain and Mental Health Program
Thalia C. Eley: King’s College London, Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience
Gerome Breen: King’s College London, Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience
Dorret I. Boomsma: Vrije Universiteit Amsterdam, Department of Complex Trait Genetics
Naomi R. Wray: University of Queensland, Institute for Molecular Bioscience
Nicholas G. Martin: QIMR Berghofer Medical Research Institute, Brain and Mental Health Program
Brittany L. Mitchell: QIMR Berghofer Medical Research Institute, Brain and Mental Health Program

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract There are striking sex differences in the prevalence and symptomology of Major Depressive Disorder. Here, we conduct the largest sex-stratified genome wide association and genotype-by-sex interaction meta-analyses of Major Depressive Disorder to date (Females: 130,471 cases, 159,521 controls. Males: 64,805 cases, 132,185 controls). We identify 16 and eight independent genome-wide significant variants in females and males, respectively, including one novel variant on the X chromosome. Major Depressive Disorder in females and males shows substantial genetic overlap with a large proportion of variants displaying similar effect sizes across sexes. However, we also provide evidence for a higher burden of genetic risk in females which could be due to female-specific variants. Additionally, sex-specific pleiotropic effects may contribute to the higher prevalence of metabolic symptoms in females with Major Depressive Disorder. These findings underscore the importance of considering sex-specific genetic architectures in the study of health conditions, including Major Depressive Disorder, paving the way for more targeted treatment strategies.

Date: 2025
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DOI: 10.1038/s41467-025-63236-1

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