FASTKD2 is associated with memory and hippocampal structure in older adults

Abstract

Memory impairment is the cardinal early feature of Alzheimer's disease, a highly prevalent disorder whose causes remain only partially understood. To identify novel genetic predictors, we used an integrative genomics approach to perform the largest study to date of human memory (n=14 781). Using a genome-wide screen, we discovered a novel association of a polymorphism in the pro-apoptotic gene FASTKD2 (fas-activated serine/threonine kinase domains 2; rs7594645-G) with better memory performance and replicated this finding in independent samples. Consistent with a neuroprotective effect, rs7594645-G carriers exhibited increased hippocampal volume and gray matter density and decreased cerebrospinal fluid levels of apoptotic mediators. The MTOR (mechanistic target of rapamycin) gene and pathways related to endocytosis, cholinergic neurotransmission, epidermal growth factor receptor signaling and immune regulation, among others, also displayed association with memory. These findings nominate FASTKD2 as a target for modulating neurodegeneration and suggest potential mechanisms for therapies to combat memory loss in normal cognitive aging and dementia.

Figure 1. Manhattan plot for the HRS discovery GWAS of immediate recall

Observed -log₁₀ p-values (y-axis) are displayed for all tested SNPs on each chromosome (x-axis). A genome-wide significant association (p<5×10⁻⁸) to immediate recall was identified on chromosome 2 within FASTKD2. Suggestive associations (p<5×10⁻⁶) were identified on additional chromosomes. Selected top associations are labeled on the plot.

Figure 2. Association and effect of rs7594645-G (FASTKD2) on immediate recall in the HRS discovery GWAS

a) All SNPs within 500 kb of FASTKD2 are plotted based on their GWAS -log₁₀ p-values, NCBI build 37 genomic position, and recombination rates calculated from the 1000 Genomes Project reference data. The color scale of r² values is used to label SNPs based on their degree of LD with rs7594645. Genes in the region are labeled with arrows denoting 5’-to-3’ orientation. b) Mean immediate recall scores (adjusted for clinical covariates and population structure) +/- standard errors are displayed based on rs7594645 genotype. Presence of the minor allele (G) of rs7594645 imparted a modest additive effect of improving memory performance and accounted for 0.5% of the phenotypic variance.

Figure 3. Effect of FASTKD2 rs7594645-G on hippocampal volume and gray matter density in 315 older healthy control participants from the ADNI

Using high resolution T1-weighted structural MRI, mean volumes and gray matter densities in the hippocampus (adjusted for age, gender, education, and intracranial volume) ± standard errors are displayed based on rs7594645 genotype. Participants with the minor allele (G) of rs7594645 displayed increased hippocampal volume and gray matter density, with a significant multivariate effect of genotype on these MRI measures (p=0.036).