Rare CNVs and phenome-wide profiling highlight brain structural divergence and phenotypical convergence

Abstract

Copy number variations (CNVs) are rare genomic deletions and duplications that can affect brain and behaviour. Previous reports of CNV pleiotropy imply that they converge on shared mechanisms at some level of pathway cascades, from genes to large-scale neural circuits to the phenome. However, existing studies have primarily examined single CNV loci in small clinical cohorts. It remains unknown, for example, how distinct CNVs escalate vulnerability for the same developmental and psychiatric disorders. Here we quantitatively dissect the associations between brain organization and behavioural differentiation across 8 key CNVs. In 534 CNV carriers, we explored CNV-specific brain morphology patterns. CNVs were characteristic of disparate morphological changes involving multiple large-scale networks. We extensively annotated these CNV-associated patterns with ~1,000 lifestyle indicators through the UK Biobank resource. The resulting phenotypic profiles largely overlap and have body-wide implications, including the cardiovascular, endocrine, skeletal and nervous systems. Our population-level investigation established brain structural divergences and phenotypical convergences of CNVs, with direct relevance to major brain disorders.

Using rare genetic mutations to revisit structural brain asymmetry

“…After exploring asymmetry patterns associated with the two CNVs (deletions at 16p11.2 and 22q11.2 loci), we investigated whether similar patterns could be observed for a broader portfolio of eight CNVs building on prior research 40,45 . Specifically, we examined duplications at the same loci (16p11.2 proximal and 22q11.2 proximal) together with deletions and duplications at the 1q21.1 distal and 15q11.2 BP1-BP2 loci (Table 1).…”

“…The substantial downstream consequences suggest that CNVs may serve as a sharp imaginggenetics tool for interrogating the effects of genetic alterations on brain physicality and behavioral differentiation 35 . Studies have already started to delineate the effects of CNVs on brain structure 36,37 and function [38][39][40] . Although CNVs are well known to impact some of the most lateralized cognitive functions, including language capacity 41 , how CNVs affect structural brain asymmetry has not yet been explored.…”

Genetic and phenotypic similarity across major psychiatric disorders: a systematic review and quantitative assessment

“…Alternative levels of observation, such as brain transcripts (RNAs) or functional brain imaging (resting-state fMRI), emerge as possibly more aligned with the shared genetic underpinnings among psychiatric conditions. This could also be interpreted in light of previous research, which noted that brain imaging profiles linked to distinct genetic psychiatric risk variants displayed only mild correlations, and yet that these same profiles were found to be associated with highly correlated phenotypic patterns [ 47 , 48 ].…”

On the Neurobiological Basis of Chronotype: Insights from a Multimodal Population Neuroscience Study

“…Dissecting the neural correlates of chronotype by LDA Our primary objective was to elucidate and characterize the neural correlates of chronotype; in other words, we aimed to investigate the coherent neurobiological distinctions between morningness and eveningness. To achieve this goal, we utilized Linear Discriminant Analysis (LDA) to identify the multivariate brain patterns associated with chronotype, separately in the three brain-imaging modalities 137,138 . LDA is a generative modeling approach that we brought to bear for telling apart morningness and eveningness.…”