Unraveling the link between CNVs, cognition and individual neuroimaging deviation scores from a population-based reference cohort

Copy number variations (CNVs) are genetic variants that can have a 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 suffer from limitations; they are unable to inform on individual variation between carriers and preclude the study of rarer variants due to their limited sample size. Here we aim to map individualized brain deviation scores in individuals with pathogenic CNVs. We 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 the UK Biobank cohort. We highlight the 1q21.1 distal deletion and duplication, as an example of our individual-level normative modeling–CNV approach. Next, we count 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. We show a high degree of heterogeneity between pathogenic CNV carriers in their implicated brain regions. For example, the cerebellum, brainstem and pallidum show large negative deviations for specific 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. This study marks a starting point in understanding the impact of pathogenic CNVs on brain phenotypes, underscoring the intricacies of these genetic variations at the individual level and providing a means to study the effects of rare CNVs in carrier individuals. Using normative modeling and focusing on individual differences, the authors explore the link between copy number variations, brain structure and cognitive abilities.