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 (rs74905: p.Pro522Arg, P = 5.38 × 10 '10, odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 '10, OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 '14, OR = 1.67, MAF cases = 0.0143, MAF controls = 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1373-1384 |
| Number of pages | 12 |
| Journal | Nature Genetics |
| Volume | 49 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2017 |
Funding
as part of collaboration between INSERM, Victor Segalen Bordeaux II University, and Sanofi-Synthelabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne regional councils, Agence Nationale de la Recherche (ANR supported the COGINUT and COVADIS projects), Fondation de France, and the joint French Ministry of Research/INSERM ‘Cohortes et Collections de Données Biologiques’ program. The Lille Genopole received an unconditional grant from Eisai and was supported by the European Joint Programme for Neurodegenerative Disease (JPND: grant MR/L501517/1). The Three-City Biological Bank was developed and maintained by the Laboratory for Genomic Analysis LAG-BRC, Institut Pasteur de Lille. GERAD/PERADES. We thank all individuals who participated in this study. Cardiff University was supported by the Alzheimer’s Society (AS; grant RF014/164) and the Medical Research Council (MRC; grants G0801418/1, MR/K013041/1, MR/L023784/1) (R. Sims is an AS Research Fellow). Cardiff University was also supported by the European Joint Programme for Neurodegenerative Disease (JPND; grant MR/L501517/1), Alzheimer’s Research UK (ARUK; grant ARUK-PG2014-1), the Welsh Assembly Government (grant SGR544:CADR), and a donation from the Moondance Charitable Foundation. Cardiff University acknowledges the support of the UK Dementia Research Institute, of which J. Williams is an associate director. Cambridge University acknowledges support from the MRC. Patient recruitment for the MRC Prion Unit/UCL Department of Neurodegenerative Disease collection was supported by the UCLH/UCL Biomedical Centre and NIHR Queen Square Dementia Biomedical Research Unit. The University of Southampton acknowledges support from the AS. King’s College London was supported by the NIHR Biomedical Research Centre for Mental Health and the Biomedical Research Unit for Dementia at the South London and Maudsley NHS Foundation Trust and by King’s College London and the MRC. ARUK and the Big Lottery Fund provided support to Nottingham University. Ulster Garden Villages, AS, ARUK, the American Federation for Aging Research, and the Northern Ireland R&D Office provided support for Queen’s University, Belfast. The Centro de Biología Molecular Severo Ochoa (CSIS-UAM), CIBERNED, Instituto de Investigación Sanitaria la Paz, University Hospital La Paz, and the Universidad Autónoma de Madrid were supported by grants from the Ministerio de Educación y Ciencia and the Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III) and by an institutional grant of the Fundación Ramón Areces to the CMBSO. We thank I. Sastre and A. Martinez-Garcia for DNA preparation, and P. Gil and P. Coria for their recruitment efforts. The Department of Neurology, University Hospital Mútua de Terrassa, was supported by CIBERNED, Instituto de Salud Carlos III, Madrid, Spain, and acknowledges M.A. Pastor (University of Navarra Medical School and Center for Applied Medical Research), M. Seijo-Martinez (Hospital do Salnes), and R. Rene, J. Gascon, and J. Campdelacreu (Hospital de Bellvitage) for providing DNA samples. The Hospital de la Sant Pau, Universitat Autònoma de Barcelona, acknowledges support from the Spanish Ministry of Economy and Competitiveness (grant PI12/01311) and from the Generalitat de Catalunya (2014SGR-235). The Santa Lucia Foundation and the Fondazione Ca’ Granda IRCCS Ospedale Policlinico, Italy, acknowledge the Italian Ministry of Health (grant RC 10.11.12.13/A). The Bonn samples are part of the German Dementia Competence Network (DCN) and the German Research Network on Degenerative Dementia (KNDD), which are funded by the German Federal Ministry of Education and Research (grants KND: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434; grants KNDD: 01GI1007A, 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). M.M.N. is a member of the German Research Foundation (DFG) cluster of excellence ImmunoSensation. Funding for Saarland University was provided by the German Federal Ministry of Education and Research (BMBF), grant 01GS08125, to M. Riemenschneider. The University of Washington was supported by grants from the US National Institutes of Health (R01-NS085419 and R01-AG044546), the Alzheimer’s Association (NIRG-11-200110), and the American Federation for Aging Research (C. Cruchaga was recipient of a New Investigator Award in Alzheimer’s disease). Brigham Young University was supported by the Alzheimer’s Association (MNIRG-11-205368), the BYU Gerontology Program, and the US National Institutes of Health (R01-AG11380, R01-AG021136, P30-S069329-01, R01-AG042611). We also acknowledge funding from the Institute of Neurology, UCL, London, who was supported in part by ARUK via an anonymous donor, and by a fellowship to R.G. The participation of D.S., M.U., and C. Masullo in the study was completely supported by Ministero della Salute, IRCCS Research Program, Ricerca Corrente 2015–2017, Linea 2 ‘Malattiecomplesse e Terapie Innovative’ and by the ‘5 × 1000’ voluntary contribution. AddNeuromed is supported by InnoMed, an Integrated Project funded by the European Union’s Sixth Framework Programme priority FP6-2004-LIFESCIHEALTH-5, Life Sciences, Genomics, and Biotechnology for Health. We are grateful to the Wellcome Trust for awarding a Principal Research Fellowship to D.C.R. (095317/Z/11/Z). M. Riemenschneider was funded by BMBF NGFN grant 01GS08125. B.N. was supported by the Fondazione Cassa di Risparmio di Pistoia e Pescia (grants 2014.0365, 2011.0264, 2013.0347). H. Hampel is supported by the AXA Research Fund, the Fondation Universite Pierre et Marie Curie, and the ‘Fondation pour la Recherche sur Alzheimer’, Paris, France. The research leading to these results has received funding from the program ‘Investissements d’Avenir’, ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6. CHARGE. Infrastructure for the CHARGE Consortium is supported in part by National Heart, Lung, and Blood Institute grant HL105756 and for the neurology working group by AG033193 and AG049505. Rotterdam (RS). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. Generation and management of the Illumina exome chip v1.0 array data for the Rotterdam Study (RS-I) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine (http://www.glimdna. org/), Erasmus MC, Rotterdam, the Netherlands. The Exome chip array data set was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, from the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO)-sponsored Netherlands Consortium for Healthy Aging (NCHA; project 050-060-810); the Netherlands Organization for Scientific Research (NWO; project 184021007); and by the Rainbow Project (RP10; Netherlands Exome Chip Project) of Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; http://www.bbmri.nl). Generation and management of GWAS genotype data for the Rotterdam Study (RS-I, RS-II, RS-III) was executed by the Human Genotyping Facility of the Genetic The Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, and R01 AG003949, NINDS grant R01 NS080820, the CurePSP Foundation, and support from the Mayo Foundation. Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson’s Disease Consortium), and the Michael J. Fox Foundation for Parkinson’s Research. Belgium sample collection. Research at the Antwerp site is funded in part by the Interuniversity Attraction Poles program of the Belgian Science Policy Office, the Foundation for Alzheimer Research (SAO-FRA), a Methusalem Excellence Grant of the Flemish Government, the Research Foundation Flanders (FWO), and the Special Research Fund of the University of Antwerp, Belgium. Authors from the Antwerp site thank the personnel of the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge, and the Departments of Neurology and Memory Clinics at the Hospital Network Antwerp and University Hospitals Leuven. Finnish sample collection. Financial support for this project was provided by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, and the Nordic Center of Excellence in Neurodegeneration. Swedish sample collection. Sample collection was financially supported in part by the Swedish Brain Power network, the Marianne and Marcus Wallenberg Foundation, the Swedish Research Council (521-2010-3134), King Gustaf V and Queen Victoria’s Foundation of Freemasons, the Regional Agreement on Medical Training and Clinical Research (ALF) between the Stockholm County Council and the Karolinska Institutet, the Swedish Brain Foundation, and the Swedish Alzheimer Foundation. AMP AD University of Florida/Mayo Clinic/Institutes of Systems Biology. For human brain donations, we thank all patients and their families, without whom this work would not have been possible. This work was supported by NIH/NIA AG046139-01 (T.E.G., N.E.-T., N.P., S.G.Y.). We thank T.G. Beach (Banner Sun Health Institute) for sharing human tissue.
ASJC Scopus subject areas
- Genetics