A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression.
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
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.
Neurosciences (Brain & Spine)
Carrasquillo, Minerva M; Allen, Mariet; Burgess, Jeremy D; Wang, Xue; Strickland, Samantha L; Aryal, Shivani; Siuda, Joanna; Kachadoorian, Michaela L; Medway, Christopher; Younkin, Curtis S; Nair, Asha; Wang, Chen; Chanana, Pritha; Serie, Daniel; Nguyen, Thuy; Lincoln, Sarah; Malphrus, Kimberly G; Morgan, Kevin; Golde, Todd E; Price, Nathan D; White, Charles C; De Jager, Philip L; Bennett, David A; Asmann, Yan W; Crook, Julia E; Petersen, Ronald C; Graff-Radford, Neill R; Dickson, Dennis W; Younkin, Steven G; and Ertekin-Taner, Nilüfer, "A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression." (2017). Articles, Abstracts, and Reports. 2427.