Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation

Joshua C Bis; Xueqiu Jian; Brian W Kunkle; Yuning Chen; Kara L Hamilton-Nelson; William S Bush; William J Salerno; Daniel Lancour; Yiyi Ma; Alan E Renton; Edoardo Marcora; John J Farrell; Yi Zhao; Liming Qu; Shahzad Ahmad; Najaf Amin; Philippe Amouyel; Gary W Beecham; Jennifer E Below; Dominique Campion; Laura Cantwell; Camille Charbonnier; Jaeyoon Chung; Paul K Crane; Carlos Cruchaga; L Adrienne Cupples; Jean-François Dartigues; Stéphanie Debette; Jean-François Deleuze; Lucinda Fulton; Stacey B Gabriel; Emmanuelle Genin; Richard A Gibbs; Alison Goate; Benjamin Grenier-Boley; Namrata Gupta; Jonathan L Haines; Aki S Havulinna; Seppo Helisalmi; Mikko Hiltunen; Daniel P Howrigan; M Arfan Ikram; Jaakko Kaprio; Jan Konrad; Amanda Kuzma; Eric S Lander; Mark Lathrop; Terho Lehtimäki; Honghuang Lin; Kari Mattila; Richard Mayeux; Donna M Muzny; Waleed Nasser; Benjamin Neale; Kwangsik Nho; Gaël Nicolas; Devanshi Patel; Margaret A Pericak-Vance; Markus Perola; Bruce M Psaty; Olivier Quenez; Farid Rajabli; Richard Redon; Christiane Reitz; Anne M Remes; Veikko Salomaa; Chloe Sarnowski; Helena Schmidt; Michael Schmidt; Reinhold Schmidt; Hilkka Soininen; Timothy A Thornton; Giuseppe Tosto; Christophe Tzourio; Sven J van der Lee; Cornelia M van Duijn; Otto Valladares; Badri Vardarajan; Li-San Wang; Weixin Wang; Ellen Wijsman; Richard K Wilson; Daniela Witten; Kim C Worley; Xiaoling Zhang; Celine Bellenguez; Jean-Charles Lambert; Mitja I Kurki; Aarno Palotie; Mark Daly; Eric Boerwinkle; Kathryn L Lunetta; Anita L Destefano; Josée Dupuis; Eden R Martin; Gerard D Schellenberg; Sudha Seshadri; Adam C Naj; Myriam Fornage; Lindsay A Farrer

doi:10.1038/s41380-018-0112-7

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Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation

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Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation

Joshua C Bis, Xueqiu Jian, Brian W Kunkle, Yuning Chen, Kara L Hamilton-Nelson, William S Bush, William J Salerno, Daniel Lancour, Yiyi Ma, Alan E Renton, …

Molecular psychiatry, Vol.25(8), pp.1859-1875

2020-08

DOI: https://doi.org/10.1038/s41380-018-0112-7

PMCID: PMC6375806

PMID: 30108311

Abstract

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10 ), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10 ), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10 ). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

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Collaboration types: 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: Biochemistry & Molecular Biology; Neurosciences; Psychiatry
ESI research areas: Neuroscience & Behavior

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Title: Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation
Creators: Joshua C Bis - Department of Medicine (General Internal Medicine), University of Washington, Seattle, WA, USA
Xueqiu Jian - Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Brian W Kunkle - John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA
Yuning Chen - Departments of Biostatistics, Boston University School of Public Health, Boston, MA, USA
Kara L Hamilton-Nelson - John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA
William S Bush - Case Western Reserve University, Cleveland Heights, OH, USA
William J Salerno - Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Daniel Lancour - Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA
Yiyi Ma - Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA
Alan E Renton - Department of Neuroscience and Ronald M Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Edoardo Marcora - Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
John J Farrell - Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA
Yi Zhao - University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Liming Qu - University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Shahzad Ahmad - Erasmus University Medical Center, Rotterdam, Netherlands
Najaf Amin - Inserm, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France
Philippe Amouyel - University Lille, U1167-Excellence Laboratory LabEx DISTALZ, Lille, France
Gary W Beecham - John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA
Jennifer E Below - Department of Medical Genetics, Vanderbilt University Medical Center, Nashville, TN, USA
Dominique Campion - Department of Research, Centre Hospitalier du Rouvray, Sotteville-lès-, Rouen, France
Laura Cantwell - University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Camille Charbonnier - Department of Genetics and CNR-MAJ, Normandie Université, UNIROUEN, Inserm U1245 and Rouen University Hospital, F 76000, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
Jaeyoon Chung - Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA
Paul K Crane - Department of Medicine (General Internal Medicine), University of Washington, Seattle, WA, USA
Carlos Cruchaga - Department of Psychiatry, Washington University, St. Louis, MO, USA
L Adrienne Cupples - National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA
Jean-François Dartigues - University of Bordeaux, Inserm, Bordeaux Population Health Research Center, team VINTAGE, UMR 1219, F-33000, Bordeaux, France
Stéphanie Debette - Department of Neurology and Institute for Neurodegenerative Diseases, Bordeaux University Hospital, Memory Clinic, F-33000, Bordeaux, France
Jean-François Deleuze - Centre National de Recherche en Génomique Humaine, Institut François Jacob, Direction de le Recherche Fondamentale, CEA, Evry, France
Lucinda Fulton - McDonnell Genome Institute, Washington University, St. Louis, MO, USA
Stacey B Gabriel - Broad Institute of MIT and Harvard, Cambridge, MA, USA
Emmanuelle Genin - Inserm UMR-1078, CHRU Brest, Université Brest, Brest, France
Richard A Gibbs - Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Alison Goate - Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Benjamin Grenier-Boley - Inserm, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France
Namrata Gupta - Broad Institute of MIT and Harvard, Cambridge, MA, USA
Jonathan L Haines - Case Western Reserve University, Cleveland Heights, OH, USA
Aki S Havulinna - National Institute for Health and Welfare, Helsinki, Finland
Seppo Helisalmi - Institute of Clinical Medicine - Neurology and Department of Neurology, University of Eastern Finland, Kuopio, Finland
Mikko Hiltunen - Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
Daniel P Howrigan - Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
M Arfan Ikram - Erasmus University Medical Center, Rotterdam, Netherlands
Jaakko Kaprio - Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Jan Konrad - Department of Psychiatry, Washington University, St. Louis, MO, USA
Amanda Kuzma - University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Eric S Lander - Broad Institute of MIT and Harvard, Cambridge, MA, USA
Mark Lathrop - McGill University and Génome Québec Innovation Centre, Montréal, Canada
Terho Lehtimäki - Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
Honghuang Lin - Department of Medicine (Computational Biomedicine), Boston University School of Medicine, Boston, MA, USA
Kari Mattila - Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
Richard Mayeux - Columbia University, New York, NY, USA
Donna M Muzny - Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Waleed Nasser - Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Benjamin Neale - Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
Kwangsik Nho - Indiana University School of Medicine, Indianapolis, IN, USA
Gaël Nicolas - Department of Genetics and CNR-MAJ, Normandie Université, UNIROUEN, Inserm U1245 and Rouen University Hospital, F 76000, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
Devanshi Patel - Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA
Margaret A Pericak-Vance - John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA
Markus Perola - University of Tartu, Estonian Genome Center, Tartu, Estonia
Bruce M Psaty - Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
Olivier Quenez - Department of Genetics and CNR-MAJ, Normandie Université, UNIROUEN, Inserm U1245 and Rouen University Hospital, F 76000, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
Farid Rajabli - John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA
Richard Redon - Inserm, CNRS, Univ. Nantes, CHU Nantes, l'institut du thorax, Nantes, France
Christiane Reitz - Columbia University, New York, NY, USA
Anne M Remes - Unit of Clinical Neuroscience, Neurology, University of Oulu and Medical Research Center, Oulu University Hospital, Oulu, Finland
Veikko Salomaa - National Institute for Health and Welfare, Helsinki, Finland
Chloe Sarnowski - Departments of Biostatistics, Boston University School of Public Health, Boston, MA, USA
Helena Schmidt - Department of Neurology, Clinical Division of Neurogeriatrics, Medical University of Graz, Graz, Austria
Michael Schmidt - John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA
Reinhold Schmidt - Department of Neurology, Clinical Division of Neurogeriatrics, Medical University of Graz, Graz, Austria
Hilkka Soininen - Department of Neurology, Kuopio University Hospital, Kuopio, Finland
Timothy A Thornton - Department of Statistics, University of Washington, Seattle, WA, USA
Giuseppe Tosto - Columbia University, New York, NY, USA
Christophe Tzourio - University of Bordeaux, Inserm, Bordeaux Population Health Research Center, team VINTAGE, UMR 1219, F-33000, Bordeaux, France
Sven J van der Lee - Erasmus University Medical Center, Rotterdam, Netherlands
Cornelia M van Duijn - Erasmus University Medical Center, Rotterdam, Netherlands
Otto Valladares - University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Badri Vardarajan - Columbia University, New York, NY, USA
Li-San Wang - University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Weixin Wang - University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Ellen Wijsman - Department of Biostatistics, University of Washington, Seattle, WA, USA
Richard K Wilson - McDonnell Genome Institute, Washington University, St. Louis, MO, USA
Daniela Witten - Department of Biostatistics, University of Washington, Seattle, WA, USA
Kim C Worley - Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Xiaoling Zhang - Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA
Celine Bellenguez - Inserm, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France
Jean-Charles Lambert - Inserm, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France
Mitja I Kurki - Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
Aarno Palotie - Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
Mark Daly - Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
Eric Boerwinkle - School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA
Kathryn L Lunetta - Departments of Biostatistics, Boston University School of Public Health, Boston, MA, USA
Anita L Destefano - Departments of Neurology, Boston University School of Medicine, Boston, MA, USA
Josée Dupuis - Departments of Biostatistics, Boston University School of Public Health, Boston, MA, USA
Eden R Martin - John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA
Gerard D Schellenberg - University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Sudha Seshadri - Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA
Adam C Naj - University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Myriam Fornage - School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA
Lindsay A Farrer - Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA. farrer@bu.Edu
Publication Details: Molecular psychiatry, Vol.25(8), pp.1859-1875
Publisher: England
Grant note: U01 HL096899 / NHLBI NIH HHS U01 HL096917 / NHLBI NIH HHS HHSN268201100007C / NHLBI NIH HHS U01 AG049505 / NIA NIH HHS U01 AG052410 / NIA NIH HHS R03 AG054936 / NIA NIH HHS P50 AG005136 / NIA NIH HHS R01 AG049607 / NIA NIH HHS R01 AG054060 / NIA NIH HHS HHSN268201100005G / NHLBI NIH HHS P50 AG005681 / NIA NIH HHS U01 HL096902 / NHLBI NIH HHS HHSN268201100011C / NHLBI NIH HHS HHSN268201100011I / NHLBI NIH HHS HHSN268201100007I / NHLBI NIH HHS U01 AG049507 / NIA NIH HHS HHSN268201100010C / NHLBI NIH HHS HHSN268201100005C / NHLBI NIH HHS HHSN268201500001I / NHLBI NIH HHS RF1 AG015473 / NIA NIH HHS P01 AG026276 / NIA NIH HHS R01 AG020098 / NIA NIH HHS N01HC25195 / NHLBI NIH HHS HHSN268201100005I / NHLBI NIH HHS P30 AG066444 / NIA NIH HHS U54 AG052427 / NIA NIH HHS R01 AG033040 / NIA NIH HHS N01HC85081 / NHLBI NIH HHS P30 AG010161 / NIA NIH HHS P30 AG066509 / NIA NIH HHS U24 AG041689 / NIA NIH HHS R01 AG054076 / NIA NIH HHS UF1 AG047133 / NIA NIH HHS N01HC85086 / NHLBI NIH HHS U01 HL080295 / NHLBI NIH HHS RF1 AG057519 / NIA NIH HHS R01 LM012535 / NLM NIH HHS R01 NS017950 / NINDS NIH HHS N01HC85083 / NHLBI NIH HHS RF1 AG053303 / NIA NIH HHS HHSN268201100012C / NHLBI NIH HHS S10 OD018522 / NIH HHS R01 AG048927 / NIA NIH HHS R01 AG033193 / NIA NIH HHS HHSN268201500001C / NHLBI NIH HHS HHSN268201100008I / NHLBI NIH HHS N01HC85080 / NHLBI NIH HHS U01 HL096814 / NHLBI NIH HHS U01 AG049506 / NIA NIH HHS R01 AG023629 / NIA NIH HHS U54 HG003079 / NHGRI NIH HHS HHSN268201100006C / NHLBI NIH HHS U01 AG052411 / NIA NIH HHS U01 AG052409 / NIA NIH HHS P30 AG010129 / NIA NIH HHS RC2 HL102419 / NHLBI NIH HHS HHSN268201200036C / NHLBI NIH HHS U01 HL130114 / NHLBI NIH HHS HHSN268200800007C / NHLBI NIH HHS N01HC55222 / NHLBI NIH HHS U01 HL096812 / NHLBI NIH HHS R01 AG015928 / NIA NIH HHS U24 AG056270 / NIA NIH HHS N01HC85082 / NHLBI NIH HHS P01 AG003991 / NIA NIH HHS P30 AG010124 / NIA NIH HHS U01 AG016976 / NIA NIH HHS U24 AG021886 / NIA NIH HHS HHSN268201100008C / NHLBI NIH HHS R01 AG017917 / NIA NIH HHS P30 AG013846 / NIA NIH HHS R01 AG025259 / NIA NIH HHS R01 AG067501 / NIA NIH HHS R01 HL105756 / NHLBI NIH HHS U54 HG003067 / NHGRI NIH HHS R01 HL070825 / NHLBI NIH HHS U01 AG032984 / NIA NIH HHS U01 AG049508 / NIA NIH HHS U01 AG006781 / NIA NIH HHS U54 HG003273 / NHGRI NIH HHS HHSN268201100009C / NHLBI NIH HHS RF1 AG044546 / NIA NIH HHS RF1 AG054023 / NIA NIH HHS N01HC85079 / NHLBI NIH HHS HHSN268201100009I / NHLBI NIH HHS
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: 30108311
PMCID: PMC6375806
Record Identifier: 991031560924302976