Genetic variants link lower segregation of brain networks to higher blood pressure and worse cognition within the general aging population

Abstract

The functional architecture of the brain is composed of distinct networks, where higher system segregation, i.e. greater differentiation of such functional networks, is associated with better cognitive performance. Aging and many neurological diseases have been associated with reduced system segregation and thus cognitive impairment. The genetic basis and risk factors of system segregation are largely unknown. Here, we present the first genome-wide association study of fMRI-assessed system segregation in 16,635 UK Biobank participants, identifying nine independent genomic loci. The 66 implicated genes were significantly downregulated in brain tissue and upregulated in vascular tissue. Of major vascular risk factors (Life's Simple 7), blood pressure showed a robust genetic correlation with system segregation. Observational and Mendelian randomization analyses confirmed a unfavourable effect of higher blood pressure on system segregation and of lower system segregation on cognition. Replication analyses in 2,414 Rotterdam Study participants supported these conclusions.

Sex differences in functional network topology over the course of aging in 37543 UK Biobank participants

“…It is located adjacent to the INPP5A gene, which is involved in calcium signaling. As a fundamental cellular mechanism, inositol calcium signaling is expected to play a role in a range of pathways that underlie functional connectivity [64]. The INPP5A has been further associated with brain age explained by changes in functional connectivity and decreased system segregation [64,69], which is consistent with our current findings.…”

“…These data are consistent with the aging process resulting in changes in sleep habits and high blood pressure [20,63], both of which have been linked to functional connectivity changes [35,64,65]. The PAX8 protein has also been associated to the regulation of multiple genes involved in thyroid hormone synthesis, which is necessary for brain development and function, for example, through processes such as neuronal differentiation, synaptogenesis, and dendritic proliferation [35].…”