Elsevier

Biological Psychiatry

Volume 77, Issue 8, 15 April 2015, Pages 749-763
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2014.08.027Get rights and content

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.

Section snippets

GWAS Study Population

Analyses were performed in 19 population-based cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (Section 2, Table S1 in Supplement 1). All subjects were aged 45 years and dementia and stroke free at cognitive assessment. The study population comprised 29,076 participants of European ancestry, including 6674 participants with paragraph recall and 24,604 participants with word list recall tests. Each cohort secured approval from institutional

GWAS of Verbal Declarative Memory

GWAS meta-analyses of verbal declarative memory comprised in total 29,076 participants (mean age 63.6 ± 7.0 years, 56.0% women; see Table S1 in Supplement 1 for detailed demographic characteristics). Quantile-quantile plots showed no evidence of spurious inflation of p values or significant population stratification (Figure S1 in Supplement 1). Genome-wide plots of p values for SNPs against their genomic position are shown in Figure S2 in Supplement 1. For replication, 10,617 participants (72.8

Principal Findings

In this first GWAS of verbal declarative memory in almost 30,000 older nondemented community adults, we observed a genome-wide significant association of the APOE locus with poorer memory performance, especially for paragraph delayed recall. Two additional associations in subsets of the total sample and for specific tests, i.e., of rs11074779 near HS3ST4 with RAVLT-dr and of rs6813517 near SPOCK3 with CERAD-dr, were replicated and reached genome-wide significance after combining discovery and

Acknowledgments and Disclosures

Aging Gene-Environment Susceptibility-Reykjavik Study: The research has been funded by National Institute on Aging contract N01-AG-12100 with contributions from National Eye Institute, National Institute on Deafness and Other Communication Disorders, and National Heart, Lung and Blood Institute; the National Institute on Aging Intramural Research Program; Hjartavernd (the Icelandic Heart Association); and the Althingi (the Icelandic Parliament).

The Atherosclerosis Risk in Communities Study: The

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