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A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing
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Journal Article
A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing
2014
Overview
Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual’s cognitive changes were constructed. One SNP—rs2075650, located in
TOMM40
(
translocase of the outer mitochondrial membrane 40 homolog
)—had a genome-wide significant association with cognitive ageing (
P
=2.5 × 10
−8
). This result was replicated in a meta-analysis of three independent Swedish cohorts (
P
=2.41 × 10
−6
). An
Apolipoprotein E
(
APOE
) haplotype (adjacent to
TOMM40
), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (
P
=2.18 × 10
−8
; females,
P
=1.66 × 10
−11
; males,
P
=0.01). Fine SNP mapping of the
TOMM40/APOE
region identified both
APOE
(rs429358;
P
=3.66 × 10
−11
) and
TOMM40
(rs11556505;
P
=2.45 × 10
−8
) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to
APOE
(rs429358). Functional genomic analysis indicated that SNPs in the
TOMM40/APOE
region have a functional, regulatory non-protein-coding effect. The
APOE
region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Aging
/ Apolipoproteins E - genetics
/ England
/ Female
/ Genetic Predisposition to Disease
/ Genome-Wide Association Study
/ Humans
/ Male
/ Medicine
/ Membrane Transport Proteins - genetics
/ Mitochondrial Precursor Protein Import Complex Proteins
/ Polymorphism, Single Nucleotide - genetics
/ Scotland
