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R47H TREM2 variant increases risk of typical early-onset Alzheimer's disease but not of prion or frontotemporal dementia.


ABSTRACT: Rare TREM2 variants are significant risk factors for Alzheimer's disease (AD).We used next generation sequencing of the whole gene (n = 700), exon 2 Sanger sequencing (n = 2634), p.R47H genotyping (n = 3518), and genome wide association study imputation (n = 13,048) to determine whether TREM2 variants are risk factors or phenotypic modifiers in patients with AD (n = 1002), frontotemporal dementia (n = 358), sporadic (n = 2500), and variant (n = 115) Creutzfeldt-Jakob disease (CJD).We confirm only p.R47H as a risk factor for AD (odds ratio or OR = 2.19; 95% confidence interval or CI = 1.04-4.51; P = .03). p.R47H does not significantly alter risk for frontotemporal dementia (OR = 0.81), variant or sporadic CJD (OR = 1.06 95%CI = 0.66-1.69) in our cohorts. Individuals with p.R47H associated AD (n = 12) had significantly earlier symptom onset than individuals with no TREM2 variants (n = 551) (55.2 years vs. 61.7 years, P = .02). We note that heterozygous p.R47H AD is memory led and otherwise indistinguishable from "typical" sporadic AD.We find p.R47H is a risk factor for AD, but not frontotemporal dementia or prion disease.

SUBMITTER: Slattery CF 

PROVIDER: S-EPMC4627504 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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R47H TREM2 variant increases risk of typical early-onset Alzheimer's disease but not of prion or frontotemporal dementia.

Slattery Catherine F CF   Beck Jonathan A JA   Harper Lorna L   Adamson Gary G   Abdi Zeinab Z   Uphill James J   Campbell Tracy T   Druyeh Ron R   Mahoney Colin J CJ   Rohrer Jonathan D JD   Kenny Janna J   Lowe Jessica J   Leung Kelvin K KK   Barnes Josephine J   Clegg Shona L SL   Blair Melanie M   Nicholas Jennifer M JM   Guerreiro Rita J RJ   Rowe James B JB   Ponto Claudia C   Zerr Inga I   Kretzschmar Hans H   Gambetti Pierluigi P   Crutch Sebastian J SJ   Warren Jason D JD   Rossor Martin N MN   Fox Nick C NC   Collinge John J   Schott Jonathan M JM   Mead Simon S  

Alzheimer's & dementia : the journal of the Alzheimer's Association 20140823 6


<h4>Background</h4>Rare TREM2 variants are significant risk factors for Alzheimer's disease (AD).<h4>Methods</h4>We used next generation sequencing of the whole gene (n = 700), exon 2 Sanger sequencing (n = 2634), p.R47H genotyping (n = 3518), and genome wide association study imputation (n = 13,048) to determine whether TREM2 variants are risk factors or phenotypic modifiers in patients with AD (n = 1002), frontotemporal dementia (n = 358), sporadic (n = 2500), and variant (n = 115) Creutzfeldt  ...[more]

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