Assessment of TREM2 rs75932628 association with Alzheimer's disease in a population-based sample: the Cache County Study

Department of Biology, Brigham Young University, Provo, UT, USA.
Neurobiology of aging (Impact Factor: 5.01). 07/2013; 34(12). DOI: 10.1016/j.neurobiolaging.2013.06.004
Source: PubMed


Recent studies have identified the rs75932628 (R47H) variant in TREM2 as an Alzheimer's disease risk factor with estimated odds ratio ranging from 2.9 to 5.1. The Cache County Memory Study is a large, population-based sample designed for the study of memory and aging. We genotyped R47H in 2974 samples (427 cases and 2540 control subjects) from the Cache County study using a custom TaqMan assay. We observed 7 heterozygous cases and 12 heterozygous control subjects with an odds ratio of 3.5 (95% confidence interval, 1.3-8.8; p = 0.0076). The minor allele frequency and population attributable fraction for R47H were 0.0029 and 0.004, respectively. This study replicates the association between R47H and Alzheimer's disease risk in a large, population-based sample, and estimates the population frequency and attributable risk of this rare variant.

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Available from: Mark T W Ebbert, Jun 15, 2015
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    • "Murcia et al., 2013; Guerreiro et al., 2013; Neumann and Daly, 2013; Zhao et al., 2013). However, TREM2 R47H mutations appear to be relatively rare occurrences and may predispose only highly selective human populations to increased risk for age-related, pro-inflammatory neurodegenerative disorders such as AD (Gonzalez Murcia et al., 2013; Guerreiro et al., 2013; Hampel and Lista, 2013; Lattante et al., 2013; Bagyinszky et al., 2014 "

    Full-text · Article · Jun 2014 · Frontiers in Aging Neuroscience
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    • "A noteworthy fact is that the most significant non-synonymous variant, R47H (rs75932628: CGC−→CAC; and minor allele frequency [MAF] < about 1%), located within exon 2 of TREM2, shows an odds ratio (OR) range of 2.0–5.0 [11] [12], which is almost equal to the risk magnitude for the APOE-␧4 allele [13] [14]. The association of this variant with LOAD [15] [16] [17] [18] [19] as well as EOAD [20] has been reproducibly confirmed in multiple Caucasian populations. As to Asians, at present there has only been one genetic association study on TREM2 variants and LOAD, a northern Han Chinese population being involved [21]. "
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    ABSTRACT: Rare non-synonymous variants of TREM2 have recently been shown to be associated with Alzheimer's disease (AD) in Caucasians. We here conducted a replication study using a well-characterized Japanese sample set, comprising 2,190 late-onset AD (LOAD) cases and 2,498 controls. We genotyped 10 non-synonymous variants (Q33X, Y38C, R47H, T66M, N68K, D87N, T96K, R98W, H157Y, and L211P) of TREM2 reported by Guerreiro et al. (2013) by means of the TaqMan and dideoxy sequencing methods. Only three variants, R47H, H157Y, and L211P, were polymorphic (range of minor allele frequency [MAF], 0.0002-0.0059); however, no significant association with LOAD was observed in these variants. Considering low MAF of variants examined and our study sample size, further genetic analysis with a larger sample set is needed to firmly evaluate whether or not TREM2 is associated with LOAD in Japanese.
    Full-text · Article · Apr 2014 · Journal of Alzheimer's disease: JAD
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    • "Given the putative role of the IgV-set domain, we separately performed an analysis for rare variant alleles in this domain. Fixed effects (Mantel-Haenszel) meta-analysis of p.R47H was performed based on raw allele data of the Belgian AD cohort and 11 additional AD cohorts published until August 1, 2013 (Benitez et al., 2013; Giraldo et al., 2013; Gonzalez Murcia et al., 2013; Guerreiro et al., 2013; Jonsson et al., 2013; Pottier et al., 2013). For cohorts for which allele counts were not given, these were derived from total sample sizes of patients and controls, minor allele frequency in controls, and odds ratios. "
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    ABSTRACT: Homozygous mutations in exon 2 of TREM2, a gene involved in Nasu-Hakola disease, can cause frontotemporal dementia (FTD). Moreover, a rare TREM2 exon 2 variant (p.R47H) was reported to increase the risk of Alzheimer's disease (AD) with an odds ratio as strong as that for APOEε4. We systematically screened the TREM2 coding region within a Belgian study on neurodegenerative brain diseases (1216 AD patients, 357 FTD patients, and 1094 controls). We observed an enrichment of rare variants across TREM2 in both AD and FTD patients compared to controls, most notably in the extracellular IgV-set domain (relative risk = 3.84 [95% confidence interval = 1.29-11.44]; p = 0.009 for AD; relative risk = 6.19 [95% confidence interval = 1.86-20.61]; p = 0.0007 for FTD). None of the rare variants individually reached significant association, but the frequency of p.R47H was increased ∼3-fold in both AD and FTD patients compared to controls, in line with previous reports. Meta-analysis including 11 previously screened AD cohorts confirmed the association of p.R47H with AD (p = 2.93×10(-17)). Our data corroborate and extend previous findings to include an increased frequency of rare heterozygous TREM2 variations in AD and FTD, and show that TREM2 variants may play a role in neurodegenerative diseases in general.
    Full-text · Article · Oct 2013 · Neurobiology of aging
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