Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
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Nature Publishing Group
2017
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| Online Access: | https://eprints.nottingham.ac.uk/40053/ |
| _version_ | 1848795975180615680 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Sims, Rebecca |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:40:37Z |
| format | Article |
| id | nottingham-40053 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:40:37Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-400532020-05-04T18:55:44Z https://eprints.nottingham.ac.uk/40053/ 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 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. Nature Publishing Group 2017-07-17 Article PeerReviewed 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 and Morgan, Kevin (2017) Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease. Nature Genetics, 49 (9). pp. 1373-1384. ISSN 1546-1718 http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3916.html doi:10.1038/ng.3916 doi:10.1038/ng.3916 |
| spellingShingle | 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 Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease |
| title | Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease |
| title_full | Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease |
| title_fullStr | Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease |
| title_full_unstemmed | Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease |
| title_short | Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease |
| title_sort | rare coding variants in plcg2, abi3 and trem2 implicate microglialmediated innate immunity in alzheimer’s disease |
| url | https://eprints.nottingham.ac.uk/40053/ https://eprints.nottingham.ac.uk/40053/ https://eprints.nottingham.ac.uk/40053/ |