Contributions of common and rare genetic variation to different measures of mood and anxiety disorder in the UK Biobank

BJPsych Open. 2025 May 9;11(3):e97. doi: 10.1192/bjo.2025.43.

ABSTRACT

BACKGROUND: Mood and anxiety disorders co-occur and share symptoms, treatments and genetic risk, but it is unclear whether combining them into a single phenotype would better capture genetic variation. The contribution of common genetic variation to these disorders has been investigated using a range of measures; however, the differences in their ability to capture variation remain unclear, while the impact of rare variation is mostly unexplored.

AIMS: We aimed to explore the contributions of common genetic variation and copy number variations associated with risk of psychiatric morbidity (P-CNVs) to different measures of internalising disorders.

METHOD: We investigated eight definitions of mood and anxiety disorder, and a combined internalising disorder, derived from self-report questionnaires, diagnostic assessments and electronic healthcare records (EHRs). Association of these definitions with polygenic risk scores (PRSs) of major depressive disorder and anxiety disorder, as well as presence of a P-CNV, was assessed.

RESULTS: The effect sizes of both PRSs and P-CNVs were similar for mood and anxiety disorder. Compared to mood and anxiety disorder, internalising disorder resulted in higher prediction accuracy for PRSs, and increased significance of associations with P-CNVs for most definitions. Comparison across the eight definitions showed that PRSs had higher prediction accuracy and effect sizes for stricter definitions, whereas P-CNVs were more strongly associated with EHR- and self-report-based definitions.

CONCLUSIONS: Future studies may benefit from using a combined internalising disorder phenotype, and may need to consider that different phenotype definitions may be more informative depending on whether common or rare variation is studied.

PMID:40341140 | DOI:10.1192/bjo.2025.43