Sex-stratified genome-wide association meta-analysis of major depressive disorder
Jodi T. Thomas, Jackson G. Thorp, Floris Huider, P Grimes, Rujia Wang, Pierre Youssef, Jonathan R. I. Coleman, Enda M. Byrne, Mark J. Adams, Hanna M. van Loo, Brenda W.J.H. Penninx, The GLAD Study, 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, Brittany L. Mitchell
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.