Genetic architecture of the structural connectome

Area of Science:

• Neurogenetics
• Connectomics
• Neuroimaging

Background:

• Long-range myelinated connections are crucial for rapid brain communication.
• The genetic underpinnings of structural brain connectivity remain largely unknown.
• Understanding genetic control is key to deciphering brain organization and function.

Purpose of the Study:

• To investigate the genetic architecture of structural brain connectivity.
• To identify genetic variants associated with white matter tract density and organization.
• To explore the neurodevelopmental pathways and functional implications of genetic influences on connectivity.

Main Methods:

• Genome-wide association studies (GWAS) on 206 structural connectivity measures from UK Biobank diffusion MRI tractography (N=26,333).
• Statistical analysis including Bonferroni correction to identify genome-wide significant variants.
• Analysis of genetic correlations with neuropsychiatric and cognitive traits, and heritability enrichment in specific cell types.

Main Results:

• Identified 30 independent genome-wide significant variants associated with structural connectivity.
• Implicated genes involved in myelination, neurite guidance, cell proliferation, migration, cytoskeletal organization, and metal transport.
• Demonstrated that structural connectivity is highly polygenic, spatially structured, and genetically correlated with neuropsychiatric and cognitive traits.

Conclusions:

• Pervasive, pleiotropic, and spatially structured genetic control of white matter connectivity exists.
• Genetic influences on connectivity are mediated by diverse neurodevelopmental pathways, including myelination and early brain development.
• These findings highlight the relevance of genetic control of structural connectivity to healthy brain function and neuropsychiatric disorders.