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
- Hanna M. van Loo
- Brenda W. J. H. Penninx
- Sarah E. Medland
- Ian B. Hickie
- Catherine M. Olsen
- David C. Whiteman
- Heather C. Whalley
- Eske M. Derks
- Thalia C. Eley
- Gerome Breen
- Dorret I. Boomsma
- Naomi R. Wray
- Nicholas G. Martin
- Brittany L. Mitchell
2025-08-26
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.