Impact of Copy Number Variants and Polygenic Risk Scores on Psychopathology in the UK Biobank.

BACKGROUND: Our understanding of the impact of copy number variants (CNVs) on psychopathology and their joint influence with polygenic risk scores (PRS) remains limited.

METHODS: The UK Biobank recruited 502,534 individuals aged 37 to 73 living in the UK between 2006 and 2010. After quality control, genotype data from 459,855 individuals were available for CNV calling. A total of 61 commonly studied recurrent neuropsychiatric CNVs were selected for analyses and examined individually and in aggregate (any CNV, deletion or duplication). CNV risk scores (CRS) were used to quantify intolerance of CNVs to haploinsufficiency. Major depressive disorder (MDD) and generalized anxiety disorder (GAD) PRS were generated for white British individuals (N=408,870). Mood/anxiety factor scores was generated using item-level questionnaire data (N=501,289).

RESULTS: CNV carriers showed higher mood/anxiety scores than non-carriers, with the largest effects seen for intolerant deletions. A total of 11 individual deletions, and 8 duplications were associated with higher mood/anxiety. Carriers of the 9p24.3 (DMRT1) duplication showed lower mood/anxiety. Associations remained significant for most CNVs when excluding individuals with psychiatric diagnoses. Nominally significant CNV×PRS interactions provided preliminary evidence that associations between select individual CNVs, but not CNVs in aggregate, and mood/anxiety may be modulated by PRS.

CONCLUSIONS: CNVs associated with risk for psychiatric disorders showed small to large effects on dimensional mood/anxiety scores in a general population cohort, even when excluding individuals with psychiatric diagnoses. CNV×PRS interactions showed that associations between select CNVs and mood/anxiety may be modulated by PRS.