A genome-wide scan for common variants affecting the rate of age-related cognitive decline

Abstract

Age-related cognitive decline is likely promoted by accumulated brain injury due to chronic conditions of aging, including neurodegenerative and vascular disease. Because common neuronal mechanisms may mediate the adaptation to diverse cerebral insults, we hypothesized that susceptibility for age-related cognitive decline may be due in part to a shared genetic network. We have therefore performed a genome-wide association study using a quantitative measure of global cognitive decline slope, based on repeated measures of 17 cognitive tests in 749 subjects from the Religious Orders Study. Top results were evaluated in 3 independent replication cohorts, consisting of 2279 additional subjects with repeated cognitive testing. As expected, we find that the Alzheimer's disease (AD) susceptibility locus, APOE, is strongly associated with rate of cognitive decline (P(DISC) = 5.6 × 10(-9); P(JOINT)= 3.7 × 10(-27)). We additionally discover a variant, rs10808746, which shows consistent effects in the replication cohorts and modestly improved evidence of association in the joint analysis (P(DISC) = 6.7 × 10(-5); P(REP) = 9.4 × 10(-3); P(JOINT) = 2.3 × 10(-5)). This variant influences the expression of 2 adjacent genes, PDE7A and MTFR1, which are potential regulators of inflammation and oxidative injury, respectively. Using aggregate measures of genetic risk, we find that known susceptibility loci for cardiovascular disease, type 2 diabetes, and inflammatory diseases are not significantly associated with cognitive decline in our cohort. Our results suggest that intermediate phenotypes, when coupled with larger sample sizes, may be a useful tool to dissect susceptibility loci for age-related cognitive decline and uncover shared molecular pathways with a role in neuronal injury.

Figure 1

Variability in the rate of age-related cognitive decline. Linear cognitive trajectories are shown for 100 random subjects from the ROS cohort, based on mixed effect modeling of repeated measures of the global cognition summary score, incorporating 17 distinct cognitive tests. Trajectories are adjusted for the effects baseline age, gender, and education. The residual cognitive decline slope was used as an outcome for the genome-wide association analysis. The distribution of the cognitive decline trait for the entire ROS discovery cohort is shown in Supplementary Figure 1.

Figure 2

A genome-wide association scan for age-related cognitive decline. Using the residual cognitive decline slope as an outcome trait, associations were evaluated for 672,266 SNPs in the discovery cohort consisting of 749 ROS subjects. (A) Quantile-quantile plot. (B) Manhattan plot. Thresholds for suggestive (P<10⁻⁴, blue) and genome-wide (P<5×10⁻⁸, red) significance are indicated.

Figure 3

Association of rs10808746 at the PDE7A/MTFR1 locus with rate of cognitive decline. (A) Mean linear trajectories of cognitive decline within the ROS discovery cohort for each of the rs10808746 genotype classes, demonstrating evidence that the rs10808746^G allele is associated with increased rate of cognitive decline. (B) Plot showing rs10808746 association peak over the PDE7A, MTFR1, and ARMC1 genes.

Figure 4

Association of rs10808746 with MTFR1 and PDE7A gene expression. The relation of rs10808746 genotype was evaluated with locus transcript levels in an available gene expression dataset from 228 subjects with demyelinating disease. The rs10808746^G allele is associated with decreased expression of MTFR1 (P=4.5×10⁻⁵) and PDE7A (P=8.4×10⁻⁴), but not ARMC1 (P=0.21).