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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; Allen, Mariet; Burgess, Jeremy D.; Medway, Christopher; Morgan, Kevin

Authors

Minerva Carrasquillo

Mariet Allen

Jeremy D. Burgess

Christopher Medway

Kevin Morgan



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.

Citation

Carrasquillo, M., Allen, M., Burgess, J. D., Medway, C., & Morgan, K. (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 and Dementia, 13(6), https://doi.org/10.1016/j.jalz.2016.10.005

Journal Article Type Article
Acceptance Date Dec 8, 2016
Online Publication Date Dec 8, 2016
Publication Date Jun 1, 2017
Deposit Date Dec 16, 2016
Publicly Available Date Mar 28, 2024
Journal Alzheimer's & Dementia
Electronic ISSN 1552-5260
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 13
Issue 6
DOI https://doi.org/10.1016/j.jalz.2016.10.005
Keywords Alzheimer's disease; eQTL; TREM2; TREML1; Regulatory variant
Public URL https://nottingham-repository.worktribe.com/output/968282
Publisher URL http://www.sciencedirect.com/science/article/pii/S1552526016330710

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