A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression.

Document Type

Article

Publication Date

6-1-2017

Publication Title

Alzheimers Dement

Keywords

Aged; Aged, 80 and over; Alzheimer Disease; Cerebellum; Female; Gene Expression; Genetic Predisposition to Disease; Genetic Variation; Humans; Linkage Disequilibrium; Male; Membrane Glycoproteins; Microarray Analysis; Multigene Family; Quantitative Trait Loci; Receptors, Immunologic; Temporal Lobe

Abstract

INTRODUCTION: We hypothesized that common Alzheimer's disease (AD)-associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression.

METHODS: Expression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis.

RESULTS: A variant within a DNase hypersensitive site 5' of TREM2, rs9357347-C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 × 10

DISCUSSION: Our findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome-wide association study meta-analysis and suggest concomitant increase in TREML1 and TREM2 brain levels as a potential mechanism for protection from AD.

Clinical Institute

Neurosciences (Brain & Spine)

Department

Geriatrics

Department

Neurosciences

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