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

Abstract

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

Methods: 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).

Results: 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.

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 PRSs.

Keywords: Anxiety; Copy number variants; Depression; Mood; Polygenic risk scores; Psychopathology.

Figure 1

Standardized mean differences between individuals with and without psychiatric diagnoses on mood/anxiety factor scores. Error bars represent standard errors. β coefficients correspond to standardized effect sizes, with values of 0.2, 0.5, and 0.8 indicating small, medium, and large effects, respectively. Diagnostic groups were compared to individuals without psychiatric diagnoses (N=451,978).

Figure 2

Standardized mean differences between CNV carriers and non-carriers on mood/anxiety factor scores. Error bars represent standard errors. β coefficients correspond to standardized effect sizes, with values of 0.2, 0.5, and 0.8 indicating small, medium, and large effects. Intolerant = CNV risk score (CRS)>2.86; Recurrent = any of the 61 neuropsychiatric recurrent CNVs; Intolerant recurrent = any of the 61 neuropsychiatric recurrent CNVs with a CRS>2.86; Recurrent rare = any of the 57 rare neuropsychiatric recurrent CNVs i.e., excluding the high frequency 2q13 (NPHP1), 15q11.2, 15q13.3 (CHRNA7), and ZNF92 CNVs; Intolerant recurrent rare = any of the 52 rare neuropsychiatric recurrent CNVs with a CRS>2.86 (i.e., excluding the high frequency CNVs listed above and the ZMYM5, CRYL1, VPS13B, 16q23.3, 17q21.31 CNVs with a CRS>2.86)

Figure 3

Effect sizes and standard errors for CNVs with FDR corrected statistically significant associations with mood/anxiety factor scores Effect sizes of 0.2, 0.5, and 0.8 indicate small, medium, and large effects, respectively. Error bars represent standard errors.

Figure 4

CNV × major depressive disorder (MDD) PRS interactions on mood/anxiety factor scores Intolerant = CNV risk score (CRS)>2.86; Recurrent = any of the 61 neuropsychiatric recurrent CNVs; Intolerant recurrent = any of the 61 neuropsychiatric recurrent CNVs with a CRS>2.86; Recurrent rare = any of the 57 rare neuropsychiatric recurrent CNVs i.e., excluding the high frequency 2q13 (NPHP1), 15q11.2, 15q13.3 (CHRNA7), and ZNF92 CNVs; Intolerant recurrent rare = any of the 52 rare neuropsychiatric recurrent CNVs with a CRS>2.86 (i.e., excluding the high frequency CNVs listed above and the ZMYM5, CRYL1, VPS13B, 16q23.3, 17q21.31 CNVs with a CRS>2.86)

Figure 5

CNV × generalized anxiety disorder (GAD) PRS interactions on mood/anxiety factor scores Intolerant = CNV risk score (CRS)>2.86; Recurrent = any of the 61 neuropsychiatric recurrent CNVs; Intolerant recurrent = any of the 61 neuropsychiatric recurrent CNVs with a CRS>2.86; Recurrent rare = any of the 57 rare neuropsychiatric recurrent CNVs i.e., excluding the high frequency 2q13 (NPHP1), 15q11.2, 15q13.3 (CHRNA7), and ZNF92 CNVs; Intolerant recurrent rare = any of the 52 rare neuropsychiatric recurrent CNVs with a CRS>2.86 (i.e., excluding the high frequency CNVs listed above and the ZMYM5, CRYL1, VPS13B, 16q23.3, 17q21.31 CNVs with a CRS>2.86).