Sex-Specific Genetic and Transcriptomic Liability to Neuroticism

Area of Science:

• Psychiatric Genetics
• Neuroscience
• Human Genetics

Background:

• Biological sex significantly influences psychiatric disorder presentation, etiology, and risk.
• Neuroticism, a transdiagnostic feature, exhibits notable sex differences in psychiatric disorders.
• Understanding sex-specific genetic and transcriptomic profiles of neuroticism is crucial.

Purpose of the Study:

• To perform genome-wide association studies (GWAS) of neuroticism separately in males and females.
• To identify sex-specific genetic and transcriptomic factors contributing to neuroticism.
• To explore the association of neuroticism polygenic scores with health outcomes and laboratory measurements.

Main Methods:

• GWAS of neuroticism conducted in 145,669 females and 129,229 males from the UK Biobank.
• Analysis considered autosomal and X chromosomal variation.
• Sex-specific effects tested using z tests, examining genetic correlates, tissue transcriptomic profiles, and polygenic associations in the Vanderbilt University Biobank.

Main Results:

• Neuroticism heritability showed no significant sex difference (females: 11.85%, males: 10.6%).
• Four female-specific (e.g., rs10736549-CNTN5) and two male-specific (e.g., rs10507274-MED13L) neuroticism risk loci reached genome-wide significance.
• Male and female neuroticism polygenic scores strongly associated with mood disorders and sex-specific erythrocyte/hemoglobin measurements.

Conclusions:

• Identified several molecular pathways partially explaining sex differences in neuroticism and psychiatric comorbidities.
• Highlighted sex-specific genetic risk loci and transcriptomic changes (e.g., SHISHA9, TEX26, NCOA6) in the pituitary gland.
• Provides a comprehensive genetic risk assessment for neuroticism, advancing understanding of sex-based variations in mental health.