A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing

被引：134

作者：

Davies, G. ^{[1
]}

Harris, S. E. ^{[2
,3
]}

Reynolds, C. A. ^{[4
]}

Payton, A. ^{[5
]}

Knight, H. M. ^{[6
]}

Liewald, D. C. ^{[1
,3
]}

Lopez, L. M. ^{[1
,3
]}

Luciano, M. ^{[1
,3
]}

Gow, A. J. ^{[1
,3
]}

Corley, J. ^{[1
]}

Henderson, R. ^{[1
]}

Murray, C. ^{[1
]}

Pattie, A. ^{[1
]}

Fox, H. C. ^{[7
]}

Redmond, P. ^{[1
]}

Lutz, M. W. ^{[8
,9
]}

Chiba-Falek, O. ^{[8
,9
]}

Linnertz, C. ^{[8
]}

Saith, S. ^{[8
]}

Haggarty, P. ^{[10
]}

McNeill, G. ^{[7
]}

Ke, X. ^{[11
]}

Ollier, W. ^{[5
]}

Horan, M. ^{[12
]}

Roses, A. D. ^{[8
,9
,13
]}

Ponting, C. P. ^{[6
]}

Porteous, D. J. ^{[2
,3
]}

Tenesa, A. ^{[14
,15
]}

Pickles, A. ^{[16
]}

Starr, J. M. ^{[3
,17
]}

Whalley, L. J. ^{[7
]}

Pedersen, N. L. ^{[18
,19
]}

Pendleton, N. ^{[12
]}

Visscher, P. M. ^{[20
,21
,22
]}

Deary, I. J. ^{[1
,3
]}

机构：

[1] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland

[2] Univ Edinburgh, Western Gen Hosp Edinburgh, Inst Genet & Mol Med, Med Genet Sect,Mol Med Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland

[3] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland

[4] Univ Calif Riverside, Dept Psychol, Riverside, CA 92521 USA

[5] Univ Manchester, Ctr Integrated Genom Med Res, Manchester, Lancs, England

[6] Univ Oxford, Dept Physiol Anat & Genet, MRC Funct Genom Unit, CGAT, Oxford, England

[7] Univ Aberdeen, Inst Appl Hlth Sci, Aberdeen, Scotland

[8] Duke Univ, Med Ctr, Dept Med, Div Neurol, Durham, NC 27710 USA

[9] Duke Univ, Joseph & Kathleen Bryan Alzheimers Dis Res Ctr, Durham, NC USA

[10] Univ Aberdeen, Rowett Inst Nutr & Hlth, Nutr & Epigenet Grp, Aberdeen, Scotland

[11] UCL, Inst Child Hlth, London, England

[12] Univ Manchester, Salford Royal NHS Fdn Trust, Sch Community Based Med, Neurodegenerat Res Grp, Salford, Lancs, England

[13] Zinfandel Pharmaceut, Chapel Hill, NC USA

[14] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH8 9JZ, Midlothian, Scotland

[15] Univ Edinburgh, Royal Dick Sch Vet Studies, Roslin Inst, Edinburgh EH8 9JZ, Midlothian, Scotland

[16] Inst Psychiat, Clin Trials Unit, London, England

[17] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland

[18] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[19] Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA

[20] Queensland Inst Med Res, Brisbane, Qld 4006, Australia

[21] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia

[22] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia

来源：

MOLECULAR PSYCHIATRY | 2014年 / 19卷 / 01期

基金：

英国医学研究理事会; 英国生物技术与生命科学研究理事会; 澳大利亚研究理事会; 英国工程与自然科学研究理事会; 英国惠康基金; 英国经济与社会研究理事会; 瑞典研究理事会;

关键词：

APOE; cognitive ageing; genetics; GWAS; TOMM40; QUANTITATIVE GENETIC-ANALYSIS; APOLIPOPROTEIN-E GENOTYPE; PROCESSING SPEED; ALZHEIMERS-DISEASE; TYPE-4; ALLELE; LATER LIFE; OLDER; ABILITIES; INTELLIGENCE; PERFORMANCE;

D O I：

10.1038/mp.2012.159

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 x 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P = 2.41 x 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 x 10(-8); females, P = 1.66 x 10(-11); males, P = 0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P = 3.66 x 10(-11)) and TOMM40 (rs11556505; P = 2.45 x 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.

引用

页码：76 / 87

页数：12

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