The genomic basis of mood instability: identification of 46 loci in 363,705 UK Biobank participants, genetic correlation with psychiatric disorders, and association with gene expression and function

Abstract

AbstractGenome-wide association studies (GWAS) of psychiatric phenotypes have tended to focus on categorical diagnoses, but to understand the biology of mental illness it may be more useful to study traits which cut across traditional boundaries. Here we report the results of a GWAS of mood instability (MI) as a trait in a large population cohort (UK Biobank, n=363,705). We also assess the clinical and biological relevance of the findings, including whether genetic associations show enrichment for nervous system pathways. Forty six unique loci associated with MI were identified with a heritability estimate of 9%. Linkage Disequilibrium Score Regression (LDSR) analyses identified genetic correlations with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia (SZ), anxiety and Post Traumatic Stress Disorder (PTSD). Gene-level and gene set analyses identified total 244 significant genes and 6 enriched gene sets. Tissue expression analysis from the SNP level data found enrichment in multiple brain regions, and eQTL analyses highlighted an inversion on chromosome 17 plus two brain-specific eQTLs. Additionally, we used a Phenotype Linkage Network (PLN) analysis and community analysis to assess for enrichment of nervous system gene sets using mouse orthologue databases. The PLN analysis found enrichment in nervous system PLNs for a community containing serotonin and melatonin receptors. In summary, this work has identified novel loci, tissues, and gene sets contributing to MI as a normal trait and will inform future work on the biology of mood and psychotic disorders, and to point the way towards potential for new stratified medicine approaches and the identification of novel trans-diagnostic drug targets.