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Sex-specific genetic and transcriptomic liability to neuroticism

  • Frank R. Wendt
    Correspondence
    Corresponding author: Frank R Wendt;
    Affiliations
    Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    VA CT Healthcare System, West Haven, CT, USA
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  • Gita A. Pathak
    Affiliations
    Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    VA CT Healthcare System, West Haven, CT, USA
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  • Kritika Singh
    Affiliations
    3 Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Murray B. Stein
    Affiliations
    VA San Diego Healthcare System, Psychiatry Service, San Diego, CA, USA

    Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA
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  • Karestan C. Koenen
    Affiliations
    Broad Institute of MIT and Harvard, Stanley Center for Psychiatry Research, Cambridge, MA, USA

    Massachusetts General Hospital, Psychiatry and Neurodevelopmental Genetics Unit (PNGU), Boston, MA, USA

    Harvard School of Public Health, Department of Epidemiology, Boston, MA, USA
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  • John H. Krystal
    Affiliations
    Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
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  • Joel Gelernter
    Affiliations
    Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    VA CT Healthcare System, West Haven, CT, USA

    Department of Genetics, Yale School of Medicine, New Haven, CT, USA

    Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA
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  • Lea K. Davis
    Affiliations
    3 Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    3 Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Renato Polimanti
    Correspondence
    Corresponding author: Renato Polimanti
    Affiliations
    Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    VA CT Healthcare System, West Haven, CT, USA
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      ABSTRACT

      Background

      The presentation, etiology, and relative risk of psychiatric disorders are strongly influenced by biological sex. Neuroticism is a transdiagnostic feature of psychiatric disorders displaying prominent sex differences. We performed genome-wide association studies (GWAS) of neuroticism separately in males and females to identify sex-specific genetic and transcriptomic profiles.

      Methods

      Neuroticism scores were derived from the Eysenck Personality Inventory Neuroticism scale. GWAS were performed in 145,669 females and 129,229 males from the UK Biobank considering autosomal and X-chromosomal variation. Two-sided Z-tests were used to test for sex-specific effects of discovered loci, genetic correlates (N=673 traits), tissue and gene transcriptomic profiles, and polygenic associations across health outcomes in the Vanderbilt University Biobank (BioVu, 39,692 females and 31,268 males).

      Results

      The SNP-heritability of neuroticism was not statistically different between males (h2=10.6%) and females (h2=11.85%). Four female-specific (rs10736549-CNTN5, rs6507056-ASXL3, rs2087182-MMS22L, and rs72995548-HSPB2) and two male-specific (rs10507274-MED13L and rs7984597) neuroticism risk loci reached genome-wide significance. Male- and female-specific neuroticism polygenic scores were most significantly associated with “mood disorders” (male OR=1.11, P=1.40x10-9; female OR=1.14, P=6.05x10-22). They also associated with sex-specific laboratory measures related to erythrocyte count, distribution, and hemoglobin concentration. Gene expression variation in the pituitary was enriched for neuroticism loci in males (males b=0.026, P=0.002) and genetically-regulated transcriptomic changes highlighted the effect of SHISHA9, TEX26, and NCOA6.

      Conclusions

      Through a comprehensive assessment of genetic risk for neuroticism and the associated biological processes, this study identified several molecular pathways that can partially explain the known sex differences in neurotic symptoms and their psychiatric comorbidities.

      Keywords

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