1. 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
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Jeremy D. Burgess, Christopher Medway, Chen Wang, Daniel J. Serie, Yan W. Asmann, Thuy Nguyen, Mariet Allen, Samantha L. Strickland, Joanna Siuda, Michaela Kachadoorian, Kevin Morgan, Kimberly G. Malphrus, David A. Bennett, Curtis S. Younkin, Xue Wang, Sarah Lincoln, Philip L. De Jager, Neill R. Graff-Radford, Dennis W. Dickson, Julia E. Crook, Pritha Chanana, Ronald C. Petersen, Nilufer Ertekin-Taner, Shivani Aryal, Steven G. Younkin, Todd E. Golde, Nathan D. Price, Asha Nair, Charles C. White, and Minerva M. Carrasquillo
- Subjects
Male ,0301 basic medicine ,Epidemiology ,TREML1 ,Regulatory variant ,Quantitative Trait Loci ,Gene Expression ,Locus (genetics) ,Biology ,Quantitative trait locus ,eQTL ,Linkage Disequilibrium ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Developmental Neuroscience ,Alzheimer Disease ,Cerebellum ,Gene cluster ,TREM2 ,Humans ,Genetic Predisposition to Disease ,Receptors, Immunologic ,Aged ,Aged, 80 and over ,Temporal cortex ,Genetics ,Membrane Glycoproteins ,Microarray analysis techniques ,Health Policy ,Genetic Variation ,Alzheimer's disease ,Microarray Analysis ,Temporal Lobe ,Psychiatry and Mental health ,030104 developmental biology ,Multigene Family ,Expression quantitative trait loci ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,Hypersensitive site ,030217 neurology & neurosurgery - 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.
- Published
- 2016
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