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. 2017 Jun;13(6):663-673. doi: 10.1016/j.jalz.2016.10.005. Epub 2016 Dec 8.


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.

Keywords: Alzheimer's disease; Regulatory variant; TREM2; TREML1; eQTL.

Publication types

  • Meta-Analysis

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism*
  • Cerebellum / metabolism
  • Female
  • Gene Expression
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Linkage Disequilibrium
  • Male
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism*
  • Microarray Analysis
  • Multigene Family
  • Quantitative Trait Loci
  • Receptors, Immunologic / genetics*
  • Receptors, Immunologic / metabolism*
  • Temporal Lobe / metabolism


  • Membrane Glycoproteins
  • Receptors, Immunologic
  • TREM2 protein, human
  • TREML1 protein, human