Sex-Specific Genetic and Transcriptomic Liability to Neuroticism

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 {beta}=0.026, P=0.002) and genetically-regulated transcriptomic changes highlighted the effect of RAB7L1, TEX26, and PLOT1.