Unraveling the Link between CNVs, General Cognition, and Individual Neuroimaging Deviation Scores from a Reference Cohort

Abstract

BackgroundCopy number variations (CNVs) are genetic variants that can have substantial influence on neurodevelopment, neuropsychiatric traits and morphometric brain changes, yet their impact at the individual level remains unknown. Common case-control approaches for analyzing CNVs often overlook individual variation between carriers and exclude rarer variants, due to their limited sample size. This study aims to map individualized brain deviation scores in individuals with pathogenic CNVs.MethodsWe used normative modeling to map neuroimaging features from several large neuroimaging datasets and applied these models to understand the neurobiological profile of CNV carriers in UK Biobank. We highlighted the 1q21.1 distal deletion and duplication, as an example of our normative modeling-CNV approach. Next, we counted the number of extreme deviations for each participant from the mean and centiles of variation from population reference norms, giving us a combined risk score per participant per imaging modality.ResultsWe show a high degree of heterogeneity between pathogenic CNV carriers in their implicated brain regions. For example, the cerebellum, brainstem and the pallidum show large negative deviations for certain 1q21.1 duplication carriers. For certain 1q21.1 deletion CNV carriers the caudate and accumbens show notable positive deviations. Finally, we show that negative deviations from these models are correlated to cognitive function.ConclusionsThis study marks a starting point in comprehending the impact of pathogenic CNVs on brain phenotypes, underscoring the intricacies of these genetic variations at the individual level and provides a means to studying the effects of rare CNVs in carrier individuals.