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; BIONIC consortium; GLAD Study; Sarah E Medland; Ian B Hickie; Catherine M Olsen; David C Whiteman; Heather C Whalley; Brenda Wjh 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

doi:10.1101/2025.05.05.25326699

Sex-stratified genome-wide association meta-analysis of Major Depressive Disorder

medRxiv [Preprint]. 2025 May 6:2025.05.05.25326699. doi: 10.1101/2025.05.05.25326699.

Authors

Jodi T Thomas^{1

2}, Jackson G Thorp^{1

2}, Floris Huider^{3

4

5}, Poppy Z Grimes⁶, Rujia Wang^{7

8}, Pierre Youssef¹, Jonathan R I Coleman^{7

8}, Enda M Byrne⁹, Mark Adams⁶; BIONIC consortium; GLAD Study; Sarah E Medland¹, Ian B Hickie¹⁰, Catherine M Olsen¹¹, David C Whiteman¹¹, Heather C Whalley⁶, Brenda Wjh Penninx^{5

12}, Hanna M van Loo¹³, Eske M Derks¹, Thalia C Eley^{7

8}, Gerome Breen^{7

8}, Dorret I Boomsma^{4

5}, Naomi R Wray^{14

15}, Nicholas G Martin¹, Brittany L Mitchell^{1

2

16}

Affiliations

¹ Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
² School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
³ Department of Biological Psychology, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands.
⁴ Department of Complex Trait Genetics, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands.
⁵ Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
⁶ Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
⁷ Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁸ National Institute for Health and Care Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Trust, London, UK.
⁹ University of Queensland, Child Health Research Centre, Brisbane, Australia.
¹⁰ Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
¹¹ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹² Department of Psychiatry, Amsterdam UMC location Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands.
¹³ Department of Psychiatry, University of Groningen, University Medical Center Groningen, 9713 Groningen, The Netherlands.
¹⁴ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
¹⁵ Department of Psychiatry, University of Oxford, Oxford, UK.
¹⁶ School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.

Abstract

There are striking sex differences in the prevalence and symptomology of Major Depressive Disorder (MDD). We conducted the largest sex-stratified genome wide association and genotype-by-sex interaction meta-analyses of MDD to date (Females: 130,471 cases, 159,521 controls. Males: 64,805 cases, 132,185 controls). We found 16 and eight independent genome-wide significant SNPs in females and males, respectively, including one novel variant on the X chromosome. MDD in females and males shows substantial genetic overlap with a large proportion of MDD 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 MDD. These findings underscore the importance of considering sex-specific genetic architectures in the study of health conditions, including MDD, paving the way for more targeted treatment strategies.

Publication types

Preprint