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Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease

Sims, Rebecca; van der Lee, Sven J.; Naj, Adam C.; Bellenguez, Céline; Badarinarayan, Nandini; Jakobsdottir, Johanna; Kunkle, Brian W.; Boland, Anne; Raybould, Rachel; Bis, Josha C.; Martin, Eden R.; Grenier-Boley, Benjamin; Medway, Christopher; Brown, Kristelle; Braae, Anne; Lord, Jenny; Turton, James; Barber, Imelda S.; Brookes, Keeley; Morgan, Kevin

Authors

Rebecca Sims

Sven J. van der Lee

Adam C. Naj

Céline Bellenguez

Nandini Badarinarayan

Johanna Jakobsdottir

Brian W. Kunkle

Anne Boland

Rachel Raybould

Josha C. Bis

Eden R. Martin

Benjamin Grenier-Boley

Christopher Medway

Kristelle Brown

Anne Braae

Jenny Lord

James Turton

Imelda S. Barber

Keeley Brookes

Kevin Morgan



Abstract

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.

Journal Article Type Article
Journal Nature Genetics
Print ISSN 1061-4036
Electronic ISSN 1546-1718
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 49
Issue 9
APA6 Citation Sims, R., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., …Morgan, K. (in press). Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease. Nature Genetics, 49(9), doi:10.1038/ng.3916
DOI https://doi.org/10.1038/ng.3916
Publisher URL http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3916.html
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
Additional Information 449 authors in total

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2017_ExomeChipPaper.pdf (204 Kb)
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2017_ExomeChipSupplementary.pdf (12.8 Mb)
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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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