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

Genome-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 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 mood instability were identified with a SNP heritability estimate of 9%. Linkage Disequilibrium Score Regression (LDSR) analyses identified genetic correlations with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia, anxiety, and Post Traumatic Stress Disorder (PTSD). Gene-level and gene set analyses identified 244 significant genes and 6 enriched gene sets. Tissue expression analysis of the SNP-level data found enrichment in multiple brain regions, and eQTL analyses highlighted an inversion on chromosome 17 plus two brain-specific eQTLs. In addition, 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 mood instability. These findings may be relevant for the identification of novel trans-diagnostic drug targets and could help to inform future stratified medicine innovations in mental health.

Genome-wide Association Study of Pediatric Obsessive-Compulsive Traits: Shared Genetic Risk between Traits and Disorder

“…Lack of power is the most likely explanation for the absence of significant results. Previous studies on other psychiatric disorders report shared genetic risk between traits and diagnoses, with polygenic risk and genetic correlations similar to what we report for OC traits and OCD case/control status [38,64,65]. The shared genetic risk between OC traits and OCD supports the hypothesis that an OCD diagnosis could represent the high extreme of OC traits that are widely distributed in the general population.…”

“…Rare CNVs in PTPRD have been identified in cases with OCD [29], ADHD [34] and with brain malformations at birth [35]. SNPs in PTPRD were genome-wise significantly associated with ASD [36], restless legs syndrome [37], and self-reported mood instability [38]. Ptprd-deficient mice show learning deficits and altered long-term potentiation magnitudes in hippocampal synapses [39].…”

From Schizophrenia Genetics to Disease Biology: Harnessing New Concepts and Technologies

“…Moreover, large-scale whole exome (WES) or genome (WGS) sequencing studies conducted on increasingly large (and more diverse) samples are anticipated in the near future to identify many new, rare SZ risk variants. Continuously larger samples are available from national biobanks, of which the UK Biobank is a stellar example of productivity [14,15]. Environmental factors (some of which can in turn be modified by genetic phenotypes of parents and children), such as level of stress, viral infections, nutritional deficits, and family cognitive characteristics may add or subtract risk, independently, or through interaction with genetic factors to increase susceptibility risk in more complex models, some including epigenomic components.…”

Clinical Correlates of False Positive Assignment in Bipolar Screening Measures Across Psychiatric Diagnoses among Patients without Bipolar Disorder

“…41 A recent study reported that emotional instability showed a significant genetic overlap with bipolar disorder, unipolar depression, and anxiety. 42 Additional studies are needed to determine the biological correlates of positive assignment by bipolar screening questionnaires.…”