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
Jackson G. Thorp: QIMR Berghofer Medical Research Institute
Floris Huider: Vrije Universiteit Amsterdam
Poppy Z. Grimes: University of Edinburgh
Rujia Wang: King’s College London
Pierre Youssef: QIMR Berghofer Medical Research Institute
Jonathan R. I. Coleman: King’s College London
Enda M. Byrne: Child Health Research Centre
Mark Adams: University of Edinburgh
Sarah E. Medland: QIMR Berghofer Medical Research Institute
Ian B. Hickie: University of Sydney
Catherine M. Olsen: QIMR Berghofer Medical Research Institute
David C. Whiteman: QIMR Berghofer Medical Research Institute
Heather C. Whalley: University of Edinburgh
Brenda W.J.H. Penninx: Amsterdam Public Health Research Institute
Hanna M. van Loo: University Medical Center Groningen
Eske M. Derks: QIMR Berghofer Medical Research Institute
Thalia C. Eley: King’s College London
Gerome Breen: King’s College London
Dorret I. Boomsma: Vrije Universiteit Amsterdam
Naomi R. Wray: University of Queensland
Nicholas G. Martin: QIMR Berghofer Medical Research Institute
Brittany L. Mitchell: QIMR Berghofer Medical Research Institute

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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