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

Alzheimers Dement

Authors	Minerva Carrasquillo Mariet Allen Jeremy Burgess Xue Wang Samantha Strickland Shivani Aryal Joanna Siuda Michaela Kachadoorian Christopher Medway Curtis Younkin Asha Nair Chen Wang Pritha Chanana Daniel Serie Thuy Nguyen Sarah Lincoln Kimberly Malphrus Kevin Morgan Todd Golde Nathan Price Charles White Philip De Jager David Bennett Yan Asmann Julia Crook Ronald Petersen Neill Graff-Radford Dennis Dickson Steven Younkin Nilüfer Ertekin-Taner
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.
Year of Publication	2016
Journal	Alzheimers Dement
Date Published	2016 Dec 08
ISSN	1552-5279
DOI	10.1016/j.jalz.2016.10.005
PubMed ID	27939925
Links
Grant list	R01 AG032990 / AG / NIA NIH HHS / United States R01 NS080820 / NS / NINDS NIH HHS / United States RF1 AG051504 / AG / NIA NIH HHS / United States U01 AG046139 / AG / NIA NIH HHS / United States