Genome-wide association study of Alzheimer's disease with psychotic symptoms

被引：92

作者：

Hollingworth, P. ^{[2
]}

Sweet, R. ^{[1
,3
,4
]}

Sims, R. ^{[2
]}

Harold, D. ^{[2
]}

Russo, G. ^{[2
]}

Abraham, R. ^{[2
]}

Stretton, A. ^{[2
]}

Jones, N. ^{[2
]}

Gerrish, A. ^{[2
]}

Chapman, J. ^{[2
]}

Ivanov, D. ^{[2
]}

Moskvina, V. ^{[2
]}

Lovestone, S. ^{[5
]}

Priotsi, P. ^{[5
]}

Lupton, M. ^{[5
]}

Brayne, C. ^{[6
]}

Gill, M. ^{[7
,8
]}

Lawlor, B. ^{[7
,8
]}

Lynch, A. ^{[7
,8
]}

Craig, D. ^{[9
]}

McGuinness, B. ^{[9
]}

Johnston, J. ^{[9
]}

Holmes, C. ^{[10
]}

Livingston, G. ^{[11
]}

Bass, N. J. ^{[11
]}

Gurling, H. ^{[11
]}

McQuillin, A. ^{[11
]}

Holmans, P. ^{[2
]}

Jones, L.

Devlin, B. ^{[1
]}

Klei, L. ^{[1
]}

Barmada, M. M. ^{[12
,13
]}

Demirci, F. Y. ^{[14
]}

DeKosky, S. T. ^{[3
,15
]}

Lopez, O. L. ^{[3
]}

Passmore, P. ^{[9
]}

Owen, M. J. ^{[2
]}

O'Donovan, M. C. ^{[2
]}

Mayeux, R. ^{[12
,13
]}

Kamboh, M. I. ^{[14
]}

Williams, J. ^{[2
]}

机构：

[1] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA

[2] Cardiff Univ, Neurosci & Mental Hlth Res Inst, Ctr Neuropsychiat Genet & Genom, Dept Psychol Med & Neurol,Sch Med,MRC, Cardiff, S Glam, Wales

[3] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA

[4] VA Pittsburgh Healthcare Syst, VISN Mental Illness Res 4, Educ & Clin Ctr MIRECC, Pittsburgh, PA USA

[5] Kings Coll London, Dept Neurosci, Inst Psychiat, London WC2R 2LS, England

[6] Univ Cambridge, Inst Publ Hlth, Cambridge, England

[7] St James Hosp, Mercers Inst Res Aging, Dublin 8, Ireland

[8] Trinity Coll Dublin, Dublin, Ireland

[9] Queens Univ Belfast, Ageing Grp, Ctr Publ Hlth, Sch Med Dent & Biomed Sci, Belfast, Antrim, North Ireland

[10] Univ Southampton, Div Clin Neurosci, Sch Med, Southampton, Hants, England

[11] UCL, Dept Mental Hlth Sci, London, England

[12] Columbia Univ, Coll Phys & Surg, Taub Inst, New York, NY USA

[13] Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY USA

[14] Univ Pittsburgh, Dept Human Genet, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA

[15] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA

来源：

MOLECULAR PSYCHIATRY | 2012年 / 17卷 / 12期

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

Alzheimer's disease; psychosis; behavioural symptoms; genome-wide association study; genetic; INCREASED FAMILIAL RISK; COMPLEMENT RECEPTOR 1; COMMON VARIANTS; URIC-ACID; NEUROPSYCHIATRIC INVENTORY; CEREBROSPINAL-FLUID; IDENTIFIES VARIANTS; NATIONAL INSTITUTE; BIPOLAR DISORDER; ONSET;

D O I：

10.1038/mp.2011.125

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：

Psychotic symptoms occur in similar to 40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on > 1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 x 10(-7); 'AD+PvControls' P=1.11 x 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 x 10(-7)) and within VSNL1 (rs4038131, P=5.9 x 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized. Molecular Psychiatry (2012) 17, 1316-1327; doi: 10.1038/mp.2011.125; published online 18 October 2011

引用

页码：1316 / 1327

页数：12

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