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.
Keywords
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Article Info
Publication History
Published online: November 25, 2014
Accepted:
August 25,
2014
Received in revised form:
August 23,
2014
Received:
December 23,
2013
Identification
Copyright
© 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
