Polygenic scores stratify ND-CNV carrier cognitive outcomes in the UK Biobank

Abstract Carriers of rare copy-number variants associated with neurodevelopmental conditions (ND-CNVs) show variable expressivity of clinical, physical, behavioural phenotypes. Findings from clinically-ascertained cohorts indicate that this may in part be explained by additional genetic variation associated with neurodevelopmental conditions. Here, the effects of additional genetic variants on ND-CNV carrier fluid intelligence (FI) scores in the UK Biobank were assessed. Polygenic scores (PGS) for cognition (PSCog), educational attainment (PSEA), and autism (PSASD) were generated using genome-wide imputation data to investigate additional common genetic variants (MAF >1%). Similarly, rare variants (MAF ≤1%) in loci associated with intellectual disability, autism, or intolerant to loss-of-function, brain expressed loci were investigated. Increased PSCog is associated with increased FI scores in all ND-CNVs (n = 1,274; P=4.92x10-7), 15q11.2 del. (n = 514; P=1.8x10-5), and 16p13.11 dup. carriers (n = 258; P=0.044). Similarly, greater PSEA is associated with increased FI scores in all ND-CNV carriers (P = 0.022), but not in the subgroups of specific ND-CNV loci. Additionally, we tested the positive predictive value of PScog and PSEA in ND-CNV carriers. Comparing the first and tenth deciles of PScog and PSEA, 13% versus 2% and 11% versus 2% of ND-CNV carriers were correctly identified with low FI scores. Furthermore, ND-CNVs in the first decile of PSCog showed a two- to five-fold increase in probability for a low FI score compared to the baseline pre-test probability. We do not observe any association of rare additional genetic variants in loci associated with intellectual disability, autism, or intolerant to loss-of-function, brain expressed loci with FI scores in ND-CNV carriers. These findings demonstrate that PGS contribute to and can stratify ND-CNV carrier cognitive outcomes in a population-based cohort.