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Rare variant aggregation highlights rare disease genes associated with brain volume variation

Wightman, D. P.; Maciel, B. A. P. C.; Brouwer, R. M.; van den Heuvel, M.; Posthuma, D.

2024-09-28 genetic and genomic medicine
10.1101/2024.09.26.24314187 medRxiv
Show abstract

Variation in brain volume is associated with common and rare disorders. Investigating the genetics of brain volume may highlight overlap between diseases and biological mechanisms that explain disease symptoms. Previous studies examining genetic variants associated with brain volume have largely focused on common variants, with rare variant studies not primarily focusing on brain volume phenotypes or focusing on large structural variants. In this study, we aggregated rare variants within genes and associated genes with 44 brain volume phenotypes in the UK Biobank (N=40,374). We found convergence between genes within the same biological pathway and convergence between common and rare variants within the same gene. Seven of the genes associated with total or regional brain volume measures were also linked with rare brain disorders in previous literature. We successfully showed that rare variants in genes linked to rare brain disorders were also associated with sub-clinical brain volume variation.

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