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

Carrasquillo, Minerva and Allen, Mariet and Burgess, Jeremy D. and Medway, Christopher and Morgan, Kevin (2017) A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression. Alzheimer's & Dementia, 13 (6). pp. 663-673. ISSN 1552-5260

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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 × 10−3 and 4.6 × 10−2, respectively). Meta-analysis on expression quantitative trait locus results from three independent data sets (n = 1006) confirmed these associations (uncorrected P = 3.4 × 10−2 and 3.5 × 10−3, Bonferroni-corrected P = 6.7 × 10−2 and 7.1 × 10−3, respectively).

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.

Item Type: Article
Keywords: Alzheimer's disease; eQTL; TREM2; TREML1; Regulatory variant
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences > School of Molecular Medical Sciences > Human Genetics Research Group
Identification Number: 10.1016/j.jalz.2016.10.005
Depositing User: Morgan, Kevin
Date Deposited: 16 Dec 2016 15:48
Last Modified: 11 Dec 2017 02:45
URI: http://eprints.nottingham.ac.uk/id/eprint/39400

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