A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease

23andMe Research Team

doi:10.1038/s41588-021-00921-z

A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease

23andMe Research Team

Vrije Universiteit Amsterdam
University of Oslo
University of California at San Diego
Haugesund Hospital, Helse Fonna, Department of Research and Innovation, Haugesund, Norway
University of Bergen
Norwegian University of Science and Technology
University of Michigan, Ann Arbor
Department of Psychiatry, Hospital Namsos, Nord-Trøndelag Health Trust, Namsos, Norway
Statens Serum Institut
Massachusetts General Hospital
King's College London
South London and Maudsley NHS Foundation Trust
University College London
University College London Hospitals, London, UK
23andMe Inc.
Vanderbilt University
Karolinska Institutet
University of California at Riverside
Jönköping University
deCODE Genetics
Landspitali University Hospital
University of Iceland
University of Gothenburg
Sahlgrenska University Hospital
Stavanger University Hospital
Vestfold Hospital Trust
Broad Institute
Charité – Universitätsmedizin Berlin
Amsterdam UMC - Vrije Universiteit Amsterdam
VU University Medical Hospital
Oslo University Hospital
Department of Neurosciences
Haugesund Hospital
University of Michigan Medical School
University of Michigan School of Public Health
Brigham and Women’s Hospital
Great Ormond St Hospital for Children NHS Trust
Vanderbilt University Medical Center
Sahlgrenska Academy
Akershus University Hospital

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Abstract

Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.

Original language	English
Pages (from-to)	1276-1282
Number of pages	7
Journal	Nature genetics
Volume	53
Issue number	9
DOIs	https://doi.org/10.1038/s41588-021-00921-z
Publication status	Published - 1 Sept 2021

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@article{f863e23dfc6f4c0190802a7149344a89,

title = "A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer{\textquoteright}s disease",

abstract = "Late-onset Alzheimer{\textquoteright}s disease is a prevalent age-related polygenic disease that accounts for 50–70\% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer{\textquoteright}s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer{\textquoteright}s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer{\textquoteright}s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer{\textquoteright}s disease to identify further genetic variants that contribute to Alzheimer{\textquoteright}s pathology.",

author = "Wightman, \{Douglas P.\} and Jansen, \{Iris E.\} and Savage, \{Jeanne E.\} and Shadrin, \{Alexey A.\} and Shahram Bahrami and Dominic Holland and Arvid Rongve and Sigrid B{\o}rte and Winsvold, \{Bendik S.\} and Drange, \{Ole Kristian\} and Martinsen, \{Amy E.\} and Skogholt, \{Anne Heidi\} and Cristen Willer and Geir Br{\aa}then and Ingunn Bosnes and Nielsen, \{Jonas Bille\} and Fritsche, \{Lars G.\} and Thomas, \{Laurent F.\} and Pedersen, \{Linda M.\} and Gabrielsen, \{Maiken E.\} and Johnsen, \{Marianne Bakke\} and Meisingset, \{Tore Wergeland\} and Wei Zhou and Petroula Proitsi and Angela Hodges and Richard Dobson and Latha Velayudhan and \{23andMe Research Team\} and Michelle Agee and Stella Aslibekyan and Elizabeth Babalola and Bell, \{Robert K.\} and Jessica Bielenberg and Katarzyna Bryc and Emily Bullis and Briana Cameron and Daniella Coker and Partida, \{Gabriel Cuellar\} and Devika Dhamija and Sayantan Das and Elson, \{Sarah L.\} and Teresa Filshtein and Kipper Fletez-Brant and Pierre Fontanillas and Will Freyman and Gandhi, \{Pooja M.\} and Barry Hicks and Hinds, \{David A.\} and Huber, \{Karen E.\} and Jewett, \{Ethan M.\} and Yunxuan Jiang and Aaron Kleinman and Katelyn Kukar and Vanessa Lane and Keng-Han Lin and Maya Lowe and Luff, \{Marie K.\} and McCreight, \{Jennifer C.\} and McIntyre, \{Matthew H.\} and McManus, \{Kimberly F.\} and Micheletti, \{Steven J.\} and Moreno, \{Meghan E.\} and Mountain, \{Joanna L.\} and Mozaffari, \{Sahar V.\} and Priyanka Nandakumar and Noblin, \{Elizabeth S.\} and Jared O{\textquoteright}Connell and Petrakovitz, \{Aaron A.\} and Poznik, \{G. David\} and Morgan Schumacher and Shastri, \{Anjali J.\} and Shelton, \{Janie F.\} and Jingchunzi Shi and Suyash Shringarpure and Chao Tian and Vinh Tran and Tung, \{Joyce Y.\} and Xin Wang and Wei Wang and Weldon, \{Catherine H.\} and Peter Wilton and Sealock, \{Julia M.\} and Davis, \{Lea K.\} and Pedersen, \{Nancy L.\} and Reynolds, \{Chandra A.\} and Karlsson, \{Ida K.\} and Sigurdur Magnusson and Hreinn Stefansson and Steinunn Thordardottir and Jonsson, \{Palmi V.\} and Jon Snaedal and Anna Zettergren and Ingmar Skoog and Silke Kern and Margda Waern and Henrik Zetterberg and Kaj Blennow and Eystein Stordal and Kristian Hveem and John-Anker Zwart and Lavinia Athanasiu and Per Selnes and Ingvild Saltvedt and Sando, \{Sigrid B.\} and Ingun Ulstein and Srdjan Djurovic and Tormod Fladby and Dag Aarsland and Geir Selb{\ae}k and Stephan Ripke and Kari Stefansson and Andreassen, \{Ole A.\} and Danielle Posthuma",

note = "Funding Information: We thank all the participants included in this study, including the participants from Finngen, GR@CE, IGAP, UKB, DemGene, TwinGene, STSA, the Gothenburg H70 Birth Cohort Studies and Clinical AD from Sweden, ANMerge, BioVU, 23andMe, HUNT, and deCODE. We thank the research participants from 23andMe who made this study possible. We thank the participants of the Norwegian Dementia Genetics Network (DemGene). This work was supported by BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012). This work was supported by the Research Council of Norway (RCN: 248980, 248778, 223273), Norwegian Regional Health Authorities, Norwegian Health Association (22731, EU JPND: PMI-AD RCN 311993); and National Institutes of Health, National Institute on Aging R01 AG08724, R01 AG17561, R01 AG028555 and R01 AG060470. We thank the International Genomics of Alzheimer{\textquoteright}s Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients and their families. The iSelect chips were funded by the French National Foundation on Alzheimer{\textquoteright}s disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Universit{\'e} de Lille 2 and the Lille University Hospital. GERAD/PERADES was supported by the Medical Research Council (grant no. 503480), Alzheimer{\textquoteright}s Research UK (grant no. 503176), the Wellcome Trust (grant no. 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) (grant nos. 01GI0102, 01GI0711, 01GI0420). CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants U01 AG032984, U24 AG021886, U01 AG016976 and the Alzheimer{\textquoteright}s Association grant ADGC–10–196728. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = sep,

day = "1",

doi = "10.1038/s41588-021-00921-z",

language = "English",

volume = "53",

pages = "1276--1282",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "9",

}

TY - JOUR

T1 - A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease

AU - Wightman, Douglas P.

AU - Jansen, Iris E.

AU - Savage, Jeanne E.

AU - Shadrin, Alexey A.

AU - Bahrami, Shahram

AU - Holland, Dominic

AU - Rongve, Arvid

AU - Børte, Sigrid

AU - Winsvold, Bendik S.

AU - Drange, Ole Kristian

AU - Martinsen, Amy E.

AU - Skogholt, Anne Heidi

AU - Willer, Cristen

AU - Bråthen, Geir

AU - Bosnes, Ingunn

AU - Nielsen, Jonas Bille

AU - Fritsche, Lars G.

AU - Thomas, Laurent F.

AU - Pedersen, Linda M.

AU - Gabrielsen, Maiken E.

AU - Johnsen, Marianne Bakke

AU - Meisingset, Tore Wergeland

AU - Zhou, Wei

AU - Proitsi, Petroula

AU - Hodges, Angela

AU - Dobson, Richard

AU - Velayudhan, Latha

AU - 23andMe Research Team

AU - Agee, Michelle

AU - Aslibekyan, Stella

AU - Babalola, Elizabeth

AU - Bell, Robert K.

AU - Bielenberg, Jessica

AU - Bryc, Katarzyna

AU - Bullis, Emily

AU - Cameron, Briana

AU - Coker, Daniella

AU - Partida, Gabriel Cuellar

AU - Dhamija, Devika

AU - Das, Sayantan

AU - Elson, Sarah L.

AU - Filshtein, Teresa

AU - Fletez-Brant, Kipper

AU - Fontanillas, Pierre

AU - Freyman, Will

AU - Gandhi, Pooja M.

AU - Hicks, Barry

AU - Hinds, David A.

AU - Huber, Karen E.

AU - Jewett, Ethan M.

AU - Jiang, Yunxuan

AU - Kleinman, Aaron

AU - Kukar, Katelyn

AU - Lane, Vanessa

AU - Lin, Keng-Han

AU - Lowe, Maya

AU - Luff, Marie K.

AU - McCreight, Jennifer C.

AU - McIntyre, Matthew H.

AU - McManus, Kimberly F.

AU - Micheletti, Steven J.

AU - Moreno, Meghan E.

AU - Mountain, Joanna L.

AU - Mozaffari, Sahar V.

AU - Nandakumar, Priyanka

AU - Noblin, Elizabeth S.

AU - O’Connell, Jared

AU - Petrakovitz, Aaron A.

AU - Poznik, G. David

AU - Schumacher, Morgan

AU - Shastri, Anjali J.

AU - Shelton, Janie F.

AU - Shi, Jingchunzi

AU - Shringarpure, Suyash

AU - Tian, Chao

AU - Tran, Vinh

AU - Tung, Joyce Y.

AU - Wang, Xin

AU - Wang, Wei

AU - Weldon, Catherine H.

AU - Wilton, Peter

AU - Sealock, Julia M.

AU - Davis, Lea K.

AU - Pedersen, Nancy L.

AU - Reynolds, Chandra A.

AU - Karlsson, Ida K.

AU - Magnusson, Sigurdur

AU - Stefansson, Hreinn

AU - Thordardottir, Steinunn

AU - Jonsson, Palmi V.

AU - Snaedal, Jon

AU - Zettergren, Anna

AU - Skoog, Ingmar

AU - Kern, Silke

AU - Waern, Margda

AU - Zetterberg, Henrik

AU - Blennow, Kaj

AU - Stordal, Eystein

AU - Hveem, Kristian

AU - Zwart, John-Anker

AU - Athanasiu, Lavinia

AU - Selnes, Per

AU - Saltvedt, Ingvild

AU - Sando, Sigrid B.

AU - Ulstein, Ingun

AU - Djurovic, Srdjan

AU - Fladby, Tormod

AU - Aarsland, Dag

AU - Selbæk, Geir

AU - Ripke, Stephan

AU - Stefansson, Kari

AU - Andreassen, Ole A.

AU - Posthuma, Danielle

N1 - Funding Information: We thank all the participants included in this study, including the participants from Finngen, GR@CE, IGAP, UKB, DemGene, TwinGene, STSA, the Gothenburg H70 Birth Cohort Studies and Clinical AD from Sweden, ANMerge, BioVU, 23andMe, HUNT, and deCODE. We thank the research participants from 23andMe who made this study possible. We thank the participants of the Norwegian Dementia Genetics Network (DemGene). This work was supported by BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012). This work was supported by the Research Council of Norway (RCN: 248980, 248778, 223273), Norwegian Regional Health Authorities, Norwegian Health Association (22731, EU JPND: PMI-AD RCN 311993); and National Institutes of Health, National Institute on Aging R01 AG08724, R01 AG17561, R01 AG028555 and R01 AG060470. We thank the International Genomics of Alzheimer’s Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients and their families. The iSelect chips were funded by the French National Foundation on Alzheimer’s disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD/PERADES was supported by the Medical Research Council (grant no. 503480), Alzheimer’s Research UK (grant no. 503176), the Wellcome Trust (grant no. 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) (grant nos. 01GI0102, 01GI0711, 01GI0420). CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants U01 AG032984, U24 AG021886, U01 AG016976 and the Alzheimer’s Association grant ADGC–10–196728. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9/1

Y1 - 2021/9/1

N2 - Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.

AB - Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.

UR - https://www.scopus.com/pages/publications/85114746630

UR - https://www.ncbi.nlm.nih.gov/pubmed/34493870

UR - https://www.scopus.com/pages/publications/85114746630

U2 - 10.1038/s41588-021-00921-z

DO - 10.1038/s41588-021-00921-z

M3 - Article

C2 - 34493870

SN - 1061-4036

VL - 53

SP - 1276

EP - 1282

JO - Nature genetics

JF - Nature genetics

IS - 9

ER -

A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease

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