Polygenic scores stratify neurodevelopmental copy number variant carrier cognitive outcomes in the UK Biobank

Abstract

Rare copy-number variants associated with neurodevelopmental conditions (ND-CNVs) exhibit variable expressivity of clinical, physical, behavioural outcomes. Findings from clinically ascertained cohorts suggest this variability may be partly due to additional genetic variation. Here, we assessed the impact of polygenic scores (PGS) and rare variants on ND-CNV carrier fluid intelligence (FI) scores in the UK Biobank. Greater PGS for cognition (PS_Cog) and educational attainment (PS_EA) is associated with increased FI scores in all ND-CNVs (n = 1317), 15q11.2 del. (n = 543), and 16p13.11 dup. carriers (n = 275). No association of rare variants associated with intellectual disability, autism, or putatively loss-of-function, brain-expressed genes was found. Positive predictive values in the first deciles of PS_cog and PS_EA showed a two- to five-fold increase in the rate of low FI scores compared to baseline rates. These findings demonstrate that PGS can stratify ND-CNV carrier cognitive outcomes in a population-based cohort.

Fig. 1. Distribution of cognition polygenic scores amongst ND-CNV carriers.

The violin-boxplots show all ND-CNV carrier (n = 1318), 15q11.2 del. carriers (n = 543), 16p13.11 dup. carriers (n = 275) and non-carrier (n = 152,325) distributions of PS_Cog (z-score). It displays the minimum (bottom of violin plot), maximum (top of violin plot), median (black line), cohort mean (purple-dashed line) and interquartile range (black bars of boxplot) of PS_Cog. The P-values shown are derived from the linear regression analyses listed in Table 2. adjusted for standard covariates (methods) and not corrected for multiple testing. * Indicates P-values that remained significant after Bonferroni correction for 12 analyses.

Fig. 2. Individual prediction of low FI scores by deciles of PGS.

PPVs (y-axis) for PS_Cog (a) and PS_EA (b) are shown here for deciles of both PGS. The proportion of low FI scores for each of the groups are as follows: ND-CNV = 0.07, Deletions = 0.06, Duplication = 0.08, 15q11.2 del. = 0.04, 16p13.11 dup. = 0.04, and non-carrier = 0.04. 95% confidence intervals are given in Supplementary Tables 17 and 18. ‘All’ indicates the baseline probability for each group.

Fig. 3. Distribution of PS_EA in all ND-CNV carriers vs non-carriers.

The violin-boxplot shows the all ND-CNV carrier (n = 1318) and non-carrier (n = 152,325) groups distributions of PS_EA (z-score). It includes summaries of minimum (bottom of violin plot), maximum (top of violin plot), group median (black line), cohort mean (purple-dashed line) and interquartile range (black bars of boxplot) of PS_EA. The p-value shown is derived from the two-sample, two-sided t-test for PS_EA (Methods). * = passed Bonferroni correction for 36 tests. See Supplementary Table 19. for full t-test results.