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Publications [#328886] of Kathleen A. Welsh-Bohmer

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Journal Articles

  1. Sims, R; van der Lee, SJ; Naj, AC; Bellenguez, C; Badarinarayan, N; Jakobsdottir, J; Kunkle, BW; Boland, A; Raybould, R; Bis, JC; Martin, ER; Grenier-Boley, B; Heilmann-Heimbach, S; Chouraki, V; Kuzma, AB; Sleegers, K; Vronskaya, M; Ruiz, A; Graham, RR; Olaso, R; Hoffmann, P; Grove, ML; Vardarajan, BN; Hiltunen, M; Nöthen, MM; White, CC; Hamilton-Nelson, KL; Epelbaum, J; Maier, W; Choi, S-H; Beecham, GW; Dulary, C; Herms, S; Smith, AV; Funk, CC; Derbois, C; Forstner, AJ; Ahmad, S; Li, H et al. (2017). Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.. Nature Genetics, 49(9), 1373-1384. [doi]
    (last updated on 2018/07/20)

    We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

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