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

Minerva M. Carrasquillo, Mariet Allen, Jeremy D. Burgess, Xue Wang, Samantha L. Strickland, Shivani Aryal, Joanna Siuda, Michaela L. Kachadoorian, Christopher Medway, Curtis S. Younkin, Asha Nair, Chen Wang, Pritha Chanana, Daniel Serie, Thuy Nguyen, Sarah Lincoln, Kimberly G. Malphrus, Kevin Morgan, Todd E. Golde, Nathan D. PriceCharles C. White, Philip L. De Jager, David A. Bennett, Yan W. Asmann, Julia E. Crook, Ronald C. Petersen, Neill R. Graff-Radford, Dennis W. Dickson, Steven G. Younkin, Nilüfer Ertekin-Taner

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)663-673
Number of pages11
JournalAlzheimer's and Dementia
Volume13
Issue number6
DOIs
StatePublished - Jun 2017

Keywords

  • Alzheimer's disease
  • Regulatory variant
  • TREM2
  • TREML1
  • eQTL

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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    Carrasquillo, M. M., Allen, M., Burgess, J. D., Wang, X., Strickland, S. L., Aryal, S., Siuda, J., Kachadoorian, M. L., Medway, C., Younkin, C. S., Nair, A., Wang, C., Chanana, P., Serie, D., Nguyen, T., Lincoln, S., Malphrus, K. G., Morgan, K., Golde, T. E., ... Ertekin-Taner, N. (2017). A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression. Alzheimer's and Dementia, 13(6), 663-673. https://doi.org/10.1016/j.jalz.2016.10.005