Rare-variant aggregation highlights disease-linked genes associated with brain volume variation.

Area of Science:

• Neurogenetics
• Brain Development
• Human Genetics

Background:

• Brain volume variation is highly heritable, with recent studies focusing on common and structural variants.
• Rare genetic variants, though less studied, often possess large effect sizes and clearer biological links to phenotypes.
• Understanding the role of rare variants is crucial for deciphering the genetic architecture of brain volume and associated disorders.

Purpose of the Study:

• To investigate the association between rare genetic variants and total and regional brain volume.
• To identify specific genes and pathways involved in brain volume regulation through rare-variant analysis.
• To explore the link between rare variants, brain volume, and the risk of rare brain diseases.

Main Methods:

• Performed rare-variant gene aggregation analysis on a large cohort (n=50,061) for 44 brain volume phenotypes.
• Analyzed both loss-of-function and missense variants to identify associations with brain volume.
• Cross-referenced identified genes with ClinVar to assess their known association with rare brain diseases and subclinical phenotypes.

Main Results:

• Identified and replicated mutations in DISP1 and SCUBE2 associated with reduced cerebellar volume, potentially via sonic hedgehog signaling.
• Found an association between PTEN mutations and macrocephaly, likely mediated by the PI3K/mTOR pathway.
• Hypothesized FA2H mutations influence cerebral white matter volume and identified 7 genes linking volume variation to rare brain diseases in ClinVar.

Conclusions:

• Rare-variant analysis is a powerful approach to uncover genes influencing brain volume and its variation.
• Specific genes (DISP1, SCUBE2, PTEN, FA2H) and pathways (sonic hedgehog, PI3K/mTOR) are implicated in regulating brain volume.
• This study provides insights into the genetic basis of brain volume regulation and its connection to rare brain disorders.