The Rare TREM2 Variant R47H Has a Modest Effect on Alzheimers Disease Risk. A. R. Parrado1, K. Mullin1, W. K. Yip2, B. Hooli1, T. Liu3, C. Lange2, L. Bertram3, R. E. Tanzi1 1) Neurology, Mass General Inst Neurodegenerative Disease, Boston, MA, USA; 2) Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA; 3) Dept. Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.

   Recently, two independent research groups (Jonsson et al. 2013 and Guerreiro et al. 2013) published results reporting a rare missense variant rs75932628 (R47H) in exon 2 of the gene encoding triggering receptor expressed on myeloid cells 2 (TREM2) significantly increase the risk for Alzheimers disease (AD) with an effect size comparable to that of the APOE 4 allele. Subsequently, Pottier et al. (2013) and Benitez et al. (2013) published independent short communications confirming the association between the minor T-allele at rs75932628 and increased risk for AD. Here we attempt to replicate the association between rs75932628 and AD risk by directly genotyping rs75932628 in two independent Caucasian family cohorts, the National Institute of Mental Health Alzheimer Disease Genetics Initiative Family Study and the National Institute on Aging Genetics Initiative for Late Onset Alzheimers Disease (NIA-LOAD) Family Study, consisting of 927 families (with 1777 affecteds and 1235 unaffecteds) and in the Caucasian NIA-LOAD case-control sample composed of 378 cases and 686 controls. Additionally, we imputed genotypes in three independent Caucasian case-control cohorts (GenADA, TGEN2, and ADNI), containing 1906 cases and 1503 controls. Meta-analysis of the two family-based and the four case-control cohorts yielded a P-value of 0.04 providing additional independent support for the association between the T-allele at rs75932628 and increased AD risk, albeit suggesting a much lower effect size (OR = 1.48, 95% CI 0.94-2.35). In conclusion, our results confirm the association between SNP rs75932628 and AD risk, however, the risk effect is substantially smaller than in the two original reports.

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