Genetic Influence underlying Brain Connectivity Phenotype: A Study on Two Age-Specific Cohorts

Abstract

Background Human brain structural connectivity is an important imaging quantitative trait for brain development and aging. Mapping the network connectivity to the phenotypic variation provides fundamental insights in understanding the relationship between detailed brain topological architecture, function, and dysfunction. However, the underlying neurobiological mechanism from gene to brain connectome, and to phenotypic outcomes, and whether this mechanism changes over time, remain unclear. Methods This study analyzes diffusion weighted imaging data from two age-specific neuroimaging cohorts, extracts structural connectome topological network measures, performs genome-wide association studies (GWAS) of the measures, and examines the causality of genetic influences on phenotypic outcomes mediated via connectivity measures. Results Our empirical study has yielded several significant findings: 1) It identified genetic makeup underlying structural connectivity changes in the human brain connectome for both age groups. Specifically, it revealed a novel association between the minor allele (G) of rs7937515 and the decreased network segregation measures of the left middle temporal gyrus across young and elderly adults, indicating a consistent genetic effect on brain connectivity across the lifespan. 2) It revealed rs7937515 as a genetic marker for body mass index (BMI) in young adults but not in elderly adults. 3) It discovered brain network segregation alterations as a potential neuroimaging biomarker for obesity. 4) It demonstrated the hemispheric asymmetry of structural network organization in genetic association analyses and outcome-relevant studies. Discussion These imaging genetic findings underlying brain connectome warrant further investigation for exploring their potential influences on brain-related diseases, given the significant involvement of altered connectivity in neurological, psychiatric and physical disorders. Impact Statement The genetic architecture underlying brain connectivity, and whether this mechanism changes over time, remain largely unknown. To understand the inter-individual variability at different life stages, this study performed genome-wide association studies of brain network connectivity measures from two age-specific neuroimaging cohorts, and identified a common association between the minor allele (G) of rs7937515 and decreased network segregation measures of the left middle temporal gyrus. The mediation analysis further elucidated neurobiological pathway of brain connectivity mediators linking the genes FAM86C1/FOLR3 with body mass index. This study provided new insights into the genetic mechanism of inter-regional connectivity alteration in the brain.