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

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.

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

Fig. 1. TREM gene cluster on Chr 6p21.1

The chromosomal positions are based on the human genome assembly from February 2009 (GRCh37/hg19). There are seven RefSeq genes at the TREM locus (TREM1, TREML1, TREM2, TREML2, TREML3P, TREML4 and TREML5P); however, TREML3P and TREML5P are non-coding pseudogenes. The transcript figures are taken from the UCSC Genome Browser.

Fig. 2. Location of TREML1 and TREM2 WG-DASL probes

The location of the (A) TREML1 and (B) TREM2 WG-DASL probes (highlighted in light blue) are shown relative to their Refseq transcripts. The chromosomal positions are based on the human genome assembly from February 2009 (GRCh37/hg19). As shown, both of these probes are complementary to all RefSeq transcripts for the respective gene. The transcript figures are taken from the UCSC Genome Browser.

Fig. 3. LD Plot of TREM locus variants

LD plot of TREM locus variants where haplotype blocks were determined with the solid spine definition; square colors correspond to D′ (tight LD=warmer colors, weak LD=cooler colors) and r² values are shown within the squares (Supplementary Methods). Red circles: The rare TREM2 AD-risk missense variants rs142232675 (p.D87N) and rs75932628 (p.R47H) [1]. Blue circles: Variants that associate with increased AD pathology burden and cognitive decline (rs7759295 and rs6910730) [14], or with lower CSF ptau (rs6922617 and rs6916710) [13]. Green circles: The variant with the most significant AD-risk association in the IGAP meta-analysis (rs9381040); rs9357347, which has the most significantTREML1 gene expression association, also shows association withTREM2 gene expression, IGAP AD-risk association and the best Regulome score within all tested SNPs; and rs9296359 which has the most significant association with TREM2 expression. RefSeq gene transcripts are shown above the LD plot relative to the variant position according to the February 2009 human genome assembly (GRCh37hg19) across the targeted genomic region (TREM gene +/−100 kb: chr6:41016999–41354457).