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

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 & Dementia: The Journal of the Alzheimer's Association, 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: Dec 16, 2016
• Journal: Alzheimer's & Dementia
• Print ISSN: 1552-5260
• Electronic ISSN: 1552-5279
• Publisher: Wiley Open Access
• 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
• Contract Date: Dec 16, 2016