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

• Published in: Biological psychiatry (1969) 2023-10, Vol.94 (7), p.591-600
• Main Authors: Mollon, Josephine, Schultz, Laura M., Huguet, Guillaume, Knowles, Emma E.M., Mathias, Samuel R., Rodrigue, Amanda, Alexander-Bloch, Aaron, Saci, Zohra, Jean-Louis, Martineau, Kumar, Kuldeep, Douard, Elise, Almasy, Laura, Jacquemont, Sebastien, Glahn, David C.
• Format: Article
• Language: English
• Subjects: Anxiety; Biological Specimen Banks; Copy number variants; Depression; Depressive Disorder, Major; DNA Copy Number Variations - genetics; Humans; Mental Disorders - genetics; Mood; Polygenic risk scores; Psychopathology; Risk Factors; United Kingdom
• ISSN: 0006-3223; 1873-2402; 1873-2402
• DOI: 10.1016/j.biopsych.2023.01.028

Our understanding of the impact of copy number variants (CNVs) on psychopathology and their joint influence with polygenic risk scores (PRSs) remains limited. The UK Biobank recruited 502,534 individuals ages 37 to 73 years living in the United Kingdom 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 were used to quantify intolerance of CNVs to haploinsufficiency. Major depressive disorder and generalized anxiety disorder PRSs were generated for White British individuals (N = 408,870). Mood/anxiety factor scores were generated using item-level questionnaire data (N = 501,289). CNV carriers showed higher mood/anxiety scores than noncarriers, 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 PRSs. 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 PRSs.