Abstract
Mood instability is a core clinical feature of affective disorders, particularly major depressive disorder (MDD) and bipolar disorder (BD). It may be a useful construct in line with the Research Domain Criteria (RDoC) approach, which proposes studying dimensional psychopathological traits that cut across diagnostic categories as a more effective strategy for identifying the underlying biology of psychiatric disorders. Here we report a genome-wide association study (GWAS) of mood instability in a very large study of 53,525 cases and 60,443 controls from the UK Biobank cohort, the only such GWAS reported to date. We identified four independent loci (on chromosomes eight, nine, 14 and 18) significantly associated with mood instability, with a common SNP-based heritability estimate for mood instability of approximately 8%. We also found a strong genetic correlation between mood instability and MDD (0.60, SE=0.07, p=8.95x10-17), a small but statistically significant genetic correlation with schizophrenia (0.11, SE=0.04, p=0.01), but no genetic correlation with BD. Several candidate genes harbouring variants in linkage disequilibrium with the associated loci may have a role in the pathophysiology of mood disorders, including the DCC netrin 1 receptor (DCC), eukaryotic initiation factor 2B (EIF2B2), placental growth factor (PGF) and protein tyrosine phosphatase, receptor type D (PTPRD) genes. Strengths of this study include the large sample size; however, our measure of mood instability may be limited by the use of a single self-reported question. Overall, this work suggests a polygenic basis for mood instability and opens up the field for the further biological investigation of this important cross-diagnostic psychopathological trait.
- Posted March 17, 2017.
