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

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 (Lifes 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.