Format

Send to

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

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

Author information

1
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
2
Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, FL, USA.
3
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA; Human Genetics Group, University of Nottingham, Nottingham, UK.
4
Department of Health Sciences Research, Mayo Clinic Rochester, MN, USA.
5
Human Genetics Group, University of Nottingham, Nottingham, UK.
6
Department of Neuroscience, University of Florida, Gainesville, FL, USA.
7
Institute for Systems Biology, Seattle, WA, USA.
8
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
9
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA.
10
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
11
Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, USA.
12
Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA.
13
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA. Electronic address: taner.nilufer@mayo.edu.

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

PMID:
27939925
PMCID:
PMC5462884
DOI:
10.1016/j.jalz.2016.10.005
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center