ausblenden:
Schlagwörter:
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Zusammenfassung:
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 x 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 = 55.7 x 10(-10)) and replication cohorts (p
= 5.65 x 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 x 10(-8), and rs6813517 [SPOCK3], p =
2.58 x 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 similar to 40,000 older individuals revealed genome-wide
associations and suggested an involvement of immune and ubiquitin
pathways.
