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

Author

Listed:
  • Jodi T. Thomas

    (QIMR Berghofer Medical Research Institute
    The University of Queensland)

  • Jackson G. Thorp

    (QIMR Berghofer Medical Research Institute
    The University of Queensland)

  • Floris Huider

    (Vrije Universiteit Amsterdam
    Vrije Universiteit Amsterdam
    Amsterdam Public Health Research Institute)

  • Poppy Z. Grimes

    (University of Edinburgh)

  • Rujia Wang

    (King’s College London
    South London and Maudsley NHS Trust)

  • Pierre Youssef

    (QIMR Berghofer Medical Research Institute)

  • Jonathan R. I. Coleman

    (King’s College London
    South London and Maudsley NHS Trust)

  • 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
    Amsterdam UMC location Vrije Universiteit Amsterdam)

  • Hanna M. van Loo

    (University Medical Center Groningen)

  • Eske M. Derks

    (QIMR Berghofer Medical Research Institute)

  • Thalia C. Eley

    (King’s College London
    South London and Maudsley NHS Trust)

  • Gerome Breen

    (King’s College London
    South London and Maudsley NHS Trust)

  • Dorret I. Boomsma

    (Vrije Universiteit Amsterdam
    Amsterdam Public Health Research Institute)

  • Naomi R. Wray

    (University of Queensland
    University of Oxford)

  • Nicholas G. Martin

    (QIMR Berghofer Medical Research Institute)

  • Brittany L. Mitchell

    (QIMR Berghofer Medical Research Institute
    The University of Queensland
    Queensland University of Technology)

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.

Suggested Citation

  • 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, 2025. "Sex-stratified genome-wide association meta-analysis of major depressive disorder," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63236-1
    DOI: 10.1038/s41467-025-63236-1
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