Genetic factors associated with higher segregation of brain networks and cognition mediated by cardiovascular health: GWAS and Mendelian randomization analyses in the UK Biobank and Rotterdam Study.

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Higher segregation of functional networks in the brain has been associated with better cognitive abilities in aging (Chan, PNAS, 2014) and higher cognitive resilience against Alzheimer's disease (Ewers, Brain, in press). Here, we elucidated for the first time the genetic and environmental (i.e. cardiovascular) determinants of system segregation (SyS) in two large population-based cohorts. We included 16,635 UK Biobank (UKB) participants (45-81y, discovery-sample) and 2,414 Rotterdam-Study participants (52-90y, replication-sample). Resting-state-fMRI SyS was computed as the ratio of between-network to within-network connectivity, where networks (N=55) were defined by independent component analysis. Genome-wide association study (GWAS) of SyS was performed in UKB, controlling for twenty principal components, age, sex, genotype-array and assessment center. For out-of-sample prediction, a polygenic risk score (PRS) of SyS was tested in Rotterdam-Study participants. In both cohorts, we determined the effect of cardiovascular health (adherence to Life's simple 7) on SyS. We estimated age-dependent and -independent effects of SyS on cognition (multi-domain factor score) in both cohorts and, in a subsample of 2,113 UKB participants, on cognitive decline over time. To explore causal effects, Mendelian Randomization (MR) analyses were performed. GWAS of SyS in UKB yielded 659 genome-wide significant single-nucleotide polymorphisms (SNPs; P<5e-08, h2 =0.144, Fig. 1). Nine independent risk loci were detected implicated 59 genes. Lead SNPs with highest likelihood to have deleterious consequences were located near the INPP5A and PLCE1 genes. In Rotterdam-Study participants, PRS explained 1.4% of variance in SyS. We found overall better cardiovascular health to be associated with higher SyS, while higher blood pressure alone was a significant predictor of lower SyS (UKB:βstd =-0.059(0.007), P<0.001; Rotterdam-Study:βstd (SE)=-0.060(0.020), P=0.003; Fig. 2). MR analysis in UKB confirmed that genetically elevated levels of blood pressure were associated with lower SyS (β(CI95%)=-0.003(-0.002,-0.001), P=0.002). We found higher SyS to be associated with better cognition across all ages in UKB (βstd (SE)=-0.031(0.012), P=0.005) and in older, but not younger Rotterdam-Study participants (βstd (SE)=0.038(0.016), P=0.0026, Fig. 3). In MR analysis, genetically elevated levels of SyS were associated with better cognition (β(CI95)=0.104(0.03-0.18), P=0.008). The current study highlights the importance of cardiovascular health for maintaining segregated brain systems what in turn was shown to benefit cognitive functions during aging.