Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

Abstract

BACKGROUND Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia-and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10−6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10−10) and replication cohorts (p = 5.65 × 10−8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10−8, and rs6813517 [SPOCK3], p = 2.58 × 10−8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS This largest study to date exploring the genetics of memory function in ~ 40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

Genetics of human memory functions in healthy cohorts

“…[48]. Interestingly, many genes identified through genome-wide screening are involved in well-known memory-related molecular pathways such as protein phosphorylation, calcium-responsive transcriptional activation, and -in generalsynaptic plasticity.…”

Cognitive genomics: Searching for the genetic roots of neuropsychological functioning.

“…Debette and colleagues (2015) examined 29,076 dementia- and stroke-free individuals of European ancestry (>45 years of age) and identified a single locus on chromosome 19 near the APOE locus. This locus is associated with poorer delayed recall performance in discovery and replication samples (Debette et al, 2015).…”

Genetic contributions to Trail Making Test performance in UK Biobank

“…32 LD score regression was also used to estimate genetic correlations between trail making measures in UK Biobank and trail making part A, trail making part B, general cognitive function, processing speed and memory from the CHARGE consortium (participants aged 45 years or older) meta-analyses of these cognitive phenotypes. 31,33,51 Gene-based association analysis MAGMA 52 was used to derive gene-based associations using the summary results of the three GWAS for trail making. Genes (18 354) were analysed after the SNPs were assigned a gene based on their position using the Genetic contributions to TMT performance SP Hagenaars et al NCBI 37.3 build, without additional boundaries placed around the genes.…”

“…The gene-based associations for trail making were compared with gene-based associations for VNR and with the gene-based associations for trail making, general cognitive function, processing speed and memory from the CHARGE consortium, based on the GWAS summary results. 31,33,51 The CHARGE summary results were converted from HapMap2 to 1000G format, to ensure the maximum overlap between the two samples. This was achieved using the LiftOver programme, which converts coordinate ranges between genome assemblies.…”