Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Rebecca Sims; Sven Van der Lee; Adam Naj; Céline Bellenguez; Nandini Badarinarayan; Johanna Jakobsdottir; Brian Kunkle; Anne Boland; Rachel Raybould; Joshua Bis; Eden Martin; Benjamin Grenier-Boley; Stefanie Heilmann-Heimbach; Vincent Chouraki; Amanda Kuzma; Kristel Sleegers; Maria Vronskaya; Agustin Ruiz; Robert Graham; Robert Olaso; Per Hoffmann; Megan Grove; Badri Vardarajan; Mikko Hiltunen; Markus Nöthen; Charles White; Kara Hamilton-Nelson; Jacques Epelbaum; Wolfgang Maier; Seung-Hoan Choi; Gary Beecham; Cécile Dulary; Stefan Herms; Albert Smith; Cory Funk; Céline Derbois; Andreas Forstner; Shahzad Ahmad; Hongdong Li; Delphine Bacq; Denise Harold; Claudia Satizabal; Otto Valladares; Alessio Squassina; Rhodri Thomas; Jennifer Brody; Liming Qu; Pascual Sanchez-Juan; Taniesha Morgan; Frank Wolters; Yi Zhao; Florentino Sanchez Garcia; Nicola Denning; Myriam Fornage; John Malamon; Maria Candida Deniz Naranjo; Elisa Majounie; Thomas Mosley; Beth Dombroski; David Wallon; Michelle Lupton; Josée Dupuis; Patrice Whitehead; Laura Fratiglioni; Christopher Medway; Xueqiu Jian; Shubhabrata Mukherjee; Lina Keller; Kristelle Brown; Honghuang Lin; Laura Cantwell; Francesco Panza; Bernadette McGuinness; Sonia Moreno-Grau; Jeremy Burgess; Vincenzo Solfrizzi; Petra Proitsi; Hieab Adams; Mariet Allen; Davide Seripa; Pau Pastor; L Adrienne Cupples; Nathan Price; Didier Hannequin; Ana Frank-García; Daniel Lévy; Paramita Chakrabarty; Paolo Caffarra; Ina Giegling; Alexa Beiser; Vilmantas Giedraitis; Harald Hampel; Melissa Garcia; Xue Wang; Lars Lannfelt; Patrizia Mecocci; Gudny Eiriksdottir; Paul Crane; Florence Pasquier; Virginia Boccardi

doi:10.1038/ng.3916

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Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

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Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Rebecca Sims, Sven Van der Lee, Adam Naj, Céline Bellenguez, Nandini Badarinarayan, Johanna Jakobsdottir, Brian Kunkle, Anne Boland, Rachel Raybould, Joshua Bis, …

Nature genetics, Vol.49(9), pp.1373-1384

2017-09

DOI: https://doi.org/10.1038/ng.3916

PMCID: PMC5669039

PMID: 28714976

Abstract

Life Sciences

Neurons and Cognition

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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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.57 Alzheimer's Disease
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
Creators: Rebecca Sims - Institute of Psychological Medicine and Clinical Neurosciences
Sven Van der Lee - Erasmus University Medical Center [Rotterdam]
Adam Naj - Hospital of the University of Pennsylvania
Céline Bellenguez - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
Nandini Badarinarayan - Institute of Psychological Medicine and Clinical Neurosciences
Johanna Jakobsdottir - Icelandic Heart Association [Kopavogur, Iceland]
Brian Kunkle - John P. Hussman Institute for Human Genomics [Miami, FL, USA]
Anne Boland - Institut de Biologie François JACOB
Rachel Raybould - Institute of Psychological Medicine and Clinical Neurosciences
Joshua Bis - Department of Medicine
Eden Martin - John P. Hussman Institute for Human Genomics [Miami, FL, USA]
Benjamin Grenier-Boley - Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
Stefanie Heilmann-Heimbach - Department of Genomics [Bonn, Germany]
Vincent Chouraki - Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
Amanda Kuzma - Hospital of the University of Pennsylvania
Kristel Sleegers - Department of Molecular Genetics
Maria Vronskaya - Institute of Psychological Medicine and Clinical Neurosciences
Agustin Ruiz - Institut Català de Neurociències Aplicades [Barcelona, Spain]
Robert Graham - Well Advanced Solutions
Robert Olaso - Centre National de Génotypage
Per Hoffmann - Translational Centre for Regenerative Medicine (TRM); Department of Cell Therapy
Megan Grove - The University of Texas Health Science Center at Houston
Badri Vardarajan - Columbia University [New York]
Mikko Hiltunen - University of Eastern Finland
Markus Nöthen - Life & Brain Center - Department of Genomics
Charles White - Génétique, Reproduction et Développement
Kara Hamilton-Nelson - John P. Hussman Institute for Human Genomics
Jacques Epelbaum - Neurobiologie de la Croissance et de la Senescence
Wolfgang Maier - Emmy Noether Project
Seung-Hoan Choi - Boston University [Boston]
Gary Beecham - John P. Hussman Institute for Human Genomics
Cécile Dulary - Centre National de Génotypage
Stefan Herms - Department of Genomics
Albert Smith - Icelandic Heart Association [Kopavogur, Iceland]
Cory Funk - Institute for Systems Biology [Seattle, WA, USA]
Céline Derbois - Centre National de Génotypage
Andreas Forstner - Universitätsklinikum Bonn
Shahzad Ahmad - Erasmus University Medical Center [Rotterdam]
Hongdong Li - Centre of Excellence for Robotic Vision [Canberra]
Delphine Bacq - Centre National de Génotypage
Denise Harold - Neuroscience and Mental Health Research Institute [Cardiff, UK]
Claudia Satizabal - Boston University School of Medicine
Otto Valladares - Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania
Alessio Squassina - Section of Neuroscience and Clinical Pharmacology
Rhodri Thomas - Institute of Psychological Medicine and Clinical Neurosciences
Jennifer Brody - University of Washington [Seattle]
Liming Qu - Hospital of the University of Pennsylvania
Pascual Sanchez-Juan - Department of Epidemiology and Biostatistics
Taniesha Morgan - Institute of Psychological Medicine and Clinical Neurosciences
Frank Wolters - Erasmus University Medical Center [Rotterdam]
Yi Zhao - Hospital of the University of Pennsylvania
Florentino Sanchez Garcia - Hospital Universitario Doctor Negrín [Las Palmas de Gran Canaria, Spain]
Nicola Denning - Institute of Psychological Medicine and Clinical Neurosciences
Myriam Fornage - The University of Texas Health Science Center at Houston
John Malamon - Hospital of the University of Pennsylvania
Maria Candida Deniz Naranjo - Hospital Universitario Doctor Negrín [Las Palmas de Gran Canaria, Spain]
Elisa Majounie - Department of Neurodegenerative Diseases
Thomas Mosley - University of Mississippi Medical Center
Beth Dombroski - Pathology and Laboratory Medicine [Philadelphia, PA, USA]
David Wallon - UNIROUEN - UFR Santé
Michelle Lupton - Bioinformatics
Josée Dupuis - Boston University School of Medicine
Patrice Whitehead - University of Miami [Coral Gables]
Laura Fratiglioni - Aging Research Center [Karolinska Institutet]
Christopher Medway - University of Nottingham, UK
Xueqiu Jian - University of Texas Health Science Center
Shubhabrata Mukherjee - University of Washington [Seattle]
Lina Keller - Department of Neurobiology, Caring Sciences and Society (NVS)
Kristelle Brown - University of Nottingham, UK
Honghuang Lin - Boston University School of Medicine
Laura Cantwell - Hospital of the University of Pennsylvania
Francesco Panza - University of Bari Aldo Moro
Bernadette McGuinness - Ageing Group, Centre for Public Health
Sonia Moreno-Grau - Institut Català de Neurociències Aplicades [Barcelona, Spain]
Jeremy Burgess - Mayo Clinic [Jacksonville]
Vincenzo Solfrizzi - University of Bari Aldo Moro
Petra Proitsi - Maurice Wohl Clinical Neuroscience Institut
Hieab Adams - Erasmus University Medical Center [Rotterdam]
Mariet Allen - Mayo Clinic [Jacksonville]
Davide Seripa - IRCCS "Casa Sollievo della Sofferenza"
Pau Pastor - Università degli Studi di Perugia
L Adrienne Cupples - Framingham Heart Study
Nathan Price - Institute for Systems Biology [Seattle, WA, USA]
Didier Hannequin - CHU Rouen
Ana Frank-García - Universidad Autonoma de Madrid
Daniel Lévy - National Heart, Lung, and Blood Institute [Bethesda]
Paramita Chakrabarty - University of Florida [Gainesville]
Paolo Caffarra - University of Parma
Ina Giegling - Department of Genomics
Alexa Beiser - School of Public Health [Boston]
Vilmantas Giedraitis - Uppsala University
Harald Hampel - Institut de la Mémoire et de la Maladie d'Alzheimer [Paris]
Melissa Garcia - National Institute on Aging [Bethesda, USA]
Xue Wang - Xi'an Jiaotong University
Lars Lannfelt - Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
Patrizia Mecocci - Institute of Gerontology and Geriatrics
Gudny Eiriksdottir - Icelandic Heart Association [Kopavogur, Iceland]
Paul Crane - University of Washington [Seattle]
Florence Pasquier - Troubles cognitifs dégénératifs et vasculaires - U 1171
Virginia Boccardi - Geriatric Medicine and Metabolic Diseases
Publication Details: Nature genetics, Vol.49(9), pp.1373-1384
Publisher: Nature Publishing Group
Academic Unit: Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 28714976
PMCID: PMC5669039
Record Identifier: 991031575407002976