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

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 pre...

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Veröffentlicht in:Nature genetics Jg. 53; H. 9; S. 1276 - 1282
Hauptverfasser: Wightman, Douglas P., Jansen, Iris E., Savage, Jeanne E., Shadrin, Alexey A., Bahrami, Shahram, Holland, Dominic, Rongve, Arvid, Børte, Sigrid, Winsvold, Bendik S., Drange, Ole Kristian, Martinsen, Amy E., Skogholt, Anne Heidi, Willer, Cristen, Bråthen, Geir, Bosnes, Ingunn, Nielsen, Jonas Bille, Fritsche, Lars G., Thomas, Laurent F., Pedersen, Linda M., Gabrielsen, Maiken E., Johnsen, Marianne Bakke, Meisingset, Tore Wergeland, Zhou, Wei, Proitsi, Petroula, Hodges, Angela, Dobson, Richard, Velayudhan, Latha, Heilbron, Karl, Auton, Adam, Sealock, Julia M., Davis, Lea K., Pedersen, Nancy L., Reynolds, Chandra A., Karlsson, Ida K., Magnusson, Sigurdur, Stefansson, Hreinn, Thordardottir, Steinunn, Jonsson, Palmi V., Snaedal, Jon, Zettergren, Anna, Skoog, Ingmar, Kern, Silke, Waern, Margda, Zetterberg, Henrik, Blennow, Kaj, Stordal, Eystein, Hveem, Kristian, Zwart, John-Anker, Athanasiu, Lavinia, Selnes, Per, Saltvedt, Ingvild, Sando, Sigrid B., Ulstein, Ingun, Djurovic, Srdjan, Fladby, Tormod, Aarsland, Dag, Selbæk, Geir, Ripke, Stephan, Stefansson, Kari, Andreassen, Ole A., Posthuma, Danielle
Format: Journal Article
Sprache:Englisch
Veröffentlicht: New York Nature Publishing Group US 01.09.2021
Nature Publishing Group
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ISSN:1061-4036, 1546-1718, 1546-1718
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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. A genome-wide association study performed in 1,126,563 individuals identifies seven new loci associated with Alzheimer’s disease and implicates microglia and immune cells in late-onset disease.
AbstractList 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.
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.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.
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. A genome-wide association study performed in 1,126,563 individuals identifies seven new loci associated with Alzheimer’s disease and implicates microglia and immune cells in late-onset disease.
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 for 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 which contribute to Alzheimer’s pathology.
A genome-wide association study performed in 1,126,563 individuals identifies seven new loci associated with Alzheimer's disease and implicates microglia and immune cells in late-onset disease. 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.
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. A genome-wide association study performed in 1,126,563 individuals identifies seven new loci associated with Alzheimer's disease and implicates microglia and immune cells in late-onset disease.
Audience Academic
Author Kern, Silke
Skogholt, Anne Heidi
Selbæk, Geir
Bosnes, Ingunn
Posthuma, Danielle
Winsvold, Bendik S.
Hveem, Kristian
Proitsi, Petroula
Davis, Lea K.
Heilbron, Karl
Aarsland, Dag
Fritsche, Lars G.
Pedersen, Nancy L.
Savage, Jeanne E.
Stefansson, Kari
Wightman, Douglas P.
Andreassen, Ole A.
Johnsen, Marianne Bakke
Rongve, Arvid
Dobson, Richard
Willer, Cristen
Athanasiu, Lavinia
Shadrin, Alexey A.
Sealock, Julia M.
Reynolds, Chandra A.
Ulstein, Ingun
Magnusson, Sigurdur
Saltvedt, Ingvild
Djurovic, Srdjan
Nielsen, Jonas Bille
Meisingset, Tore Wergeland
Stordal, Eystein
Børte, Sigrid
Auton, Adam
Gabrielsen, Maiken E.
Waern, Margda
Snaedal, Jon
Skoog, Ingmar
Jansen, Iris E.
Bahrami, Shahram
Fladby, Tormod
Ripke, Stephan
Hodges, Angela
Pedersen, Linda M.
Thomas, Laurent F.
Bråthen, Geir
Zettergren, Anna
Zetterberg, Henrik
Velayudhan, Latha
Zwart, John-Anker
Selnes, Per
Sando, Sigrid B.
Holland, Dominic
Zhou, Wei
Thordardottir, Steinunn
Karlsson, Ida K.
Martinsen, Amy E.
Jonsson, Palmi V.
Drange, Ole Kristian
Blennow, Kaj
Stefansson, Hreinn
AuthorAffiliation 27. Health Data Research UK London, University College London, London, UK
54. Department of Psychiatry and Psychotherapy, Charité–Universitätsmedizin, Berlin, Germany
4. Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
38. Faculty of Medicine, University of Iceland
50. NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway
28. Institute of Health Informatics, University College London, London, UK
17. Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim, Norway
29. NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust, London, UK
46. HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
12. Department of Mental Health, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
5. Department of Neurosciences, Uni
AuthorAffiliation_xml – name: 54. Department of Psychiatry and Psychotherapy, Charité–Universitätsmedizin, Berlin, Germany
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– name: 43. UK Dementia Research Institute at UCL, London, United Kingdom
– name: 48. Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway
– name: 4. Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
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– name: 2. NORMENT Centre, University of Oslo, Oslo, Norway
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– name: 55. Department of Child and Adolescent Psychiatry and Pediatric Psychology, Section Complex Trait Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam University Medical Center, Amsterdam, The Netherlands
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– name: 15. Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, 48109, MI, USA
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– name: 11. Department of Neurology, Oslo University Hospital, Oslo, Norway
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– name: 35. Institute of Gerontology and Aging Research Network – Jönköping (ARN-J), School of Health and Welfare, Jönköping University, Jönköping, Sweden
– name: 45. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
– name: 6. Department of Research and Innovation, Helse Fonna, Haugesund Hospital, Haugesund, Norway
– name: 24. Institute of Psychiatry, Psychology and Neurosciences, King’s College London
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– name: 37. Department of Geriatric Medicine, Landspitali University Hospital, Reykjavik, Iceland
– name: 53. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
– name: 32. Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
– name: 44. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
– name: 38. Faculty of Medicine, University of Iceland
– name: 41. Region Västra Götaland, Sahlgrenska University Hospital, Psychosis Clinic, Gothenburg, Sweden
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  surname: Zetterberg
  fullname: Zetterberg, Henrik
  organization: Department of Neurodegenerative Disease, UCL Institute of Neurology, UK Dementia Research Institute at UCL, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital
– sequence: 46
  givenname: Kaj
  surname: Blennow
  fullname: Blennow, Kaj
  organization: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital
– sequence: 47
  givenname: Eystein
  orcidid: 0000-0002-2443-7923
  surname: Stordal
  fullname: Stordal, Eystein
  organization: Department of Mental Health, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Department of Psychiatry, Hospital Namsos, Nord-Trøndelag Health Trust
– sequence: 48
  givenname: Kristian
  surname: Hveem
  fullname: Hveem, Kristian
  organization: K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology
– sequence: 49
  givenname: John-Anker
  orcidid: 0000-0001-5721-0154
  surname: Zwart
  fullname: Zwart, John-Anker
  organization: Institute of Clinical Medicine, University of Oslo, K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital
– sequence: 50
  givenname: Lavinia
  surname: Athanasiu
  fullname: Athanasiu, Lavinia
  organization: NORMENT Centre, University of Oslo, Division of Mental Health and Addiction, Oslo University Hospital
– sequence: 51
  givenname: Per
  surname: Selnes
  fullname: Selnes, Per
  organization: Department of Neurology, Akershus University Hospital
– sequence: 52
  givenname: Ingvild
  orcidid: 0000-0002-7897-9808
  surname: Saltvedt
  fullname: Saltvedt, Ingvild
  organization: Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Department of Geriatrics, St. Olav’s Hospital, Trondheim University Hospital
– sequence: 53
  givenname: Sigrid B.
  surname: Sando
  fullname: Sando, Sigrid B.
  organization: Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim
– sequence: 54
  givenname: Ingun
  surname: Ulstein
  fullname: Ulstein, Ingun
  organization: Department of Geriatric Medicine, Oslo University Hospital
– sequence: 55
  givenname: Srdjan
  orcidid: 0000-0002-8140-8061
  surname: Djurovic
  fullname: Djurovic, Srdjan
  organization: Department of Medical Genetics, Oslo University Hospital, NORMENT, Department of Clinical Science, University of Bergen
– sequence: 56
  givenname: Tormod
  orcidid: 0000-0002-9984-9797
  surname: Fladby
  fullname: Fladby, Tormod
  organization: Institute of Clinical Medicine, University of Oslo, Department of Neurology, Akershus University Hospital
– sequence: 57
  givenname: Dag
  surname: Aarsland
  fullname: Aarsland, Dag
  organization: Institute of Psychiatry Psychology and Neurosciences, King’s College London, Centre of Age-Related Medicine, Stavanger University Hospital
– sequence: 58
  givenname: Geir
  orcidid: 0000-0001-6511-8219
  surname: Selbæk
  fullname: Selbæk, Geir
  organization: Institute of Clinical Medicine, University of Oslo, Department of Geriatric Medicine, Oslo University Hospital, Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust
– sequence: 59
  givenname: Stephan
  orcidid: 0000-0003-3622-835X
  surname: Ripke
  fullname: Ripke, Stephan
  organization: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Department of Psychiatry and Psychotherapy, Charité–Universitätsmedizin
– sequence: 60
  givenname: Kari
  orcidid: 0000-0003-1676-864X
  surname: Stefansson
  fullname: Stefansson, Kari
  organization: deCODE Genetics/Amgen
– sequence: 61
  givenname: Ole A.
  orcidid: 0000-0002-4461-3568
  surname: Andreassen
  fullname: Andreassen, Ole A.
  organization: NORMENT Centre, University of Oslo, Institute of Clinical Medicine, University of Oslo, Division of Mental Health and Addiction, Oslo University Hospital
– sequence: 62
  givenname: Danielle
  orcidid: 0000-0001-7582-2365
  surname: Posthuma
  fullname: Posthuma, Danielle
  email: d.posthuma@vu.nl
  organization: Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU Amsterdam, Department of Child and Adolescent Psychiatry and Pediatric Psychology, Section Complex Trait Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam University Medical Center
BackLink https://www.ncbi.nlm.nih.gov/pubmed/34493870$$D View this record in MEDLINE/PubMed
https://urn.kb.se/resolve?urn=urn:nbn:se:hj:diva-54690$$DView record from Swedish Publication Index (Högskolan i Jönköping)
https://gup.ub.gu.se/publication/310534$$DView record from Swedish Publication Index (Göteborgs universitet)
http://kipublications.ki.se/Default.aspx?queryparsed=id:147752070$$DView record from Swedish Publication Index (Karolinska Institutet)
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ContentType Journal Article
Contributor Shringarpure, Suyash
Aslibekyan, Stella
Wang, Xin
Lane, Vanessa
Shelton, Janie F
Tian, Chao
O'Connell, Jared
Filshtein, Teresa
Hicks, Barry
Luff, Marie K
Shastri, Anjali J
Kukar, Katelyn
Das, Sayantan
Coker, Daniella
Tran, Vinh
Schumacher, Morgan
Wilton, Peter
Cameron, Briana
Micheletti, Steven J
Jewett, Ethan M
Jiang, Yunxuan
Tung, Joyce Y
Babalola, Elizabeth
Poznik, G David
Bielenberg, Jessica
Fletez-Brant, Kipper
Elson, Sarah L
Nandakumar, Priyanka
Wang, Wei
Partida, Gabriel Cuellar
Hinds, David A
Bell, Robert K
Moreno, Meghan E
McIntyre, Matthew H
McCreight, Jey C
Lowe, Maya
McManus, Kimberly F
Bryc, Katarzyna
Agee, Michelle
Huber, Karen E
Kleinman, Aaron
Petrakovitz, Aaron A
Freyman, Will
Shi, Jingchunzi
Bullis, Emily
Noblin, Elizabeth S
Mountain, Joanna L
Dhamija, Devika
Weldon, Catherine H
Lin, Keng-Han
Mozaffari, Sahar V
Fontanillas, Pierre
Gandhi, Pooja M
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Copyright The Author(s), under exclusive licence to Springer Nature America, Inc. 2021. corrected publication 2021, 2022
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Author Contributions Statement
These authors contributed equally to this work
DP and OAA conceived of the study. DPW performed the meta-analysis and follow-up analyses. IEJ, JES, DP and OAA supervised analyses. IEJ and JES generated the UKB data. ShBa and AAS helped with the study design. AHS, CW, JBN, LGF, MEG, KH, TWM, MBJ contributed to the organization of the HUNT data. BSW, AEM, OKD, GB, IB, ES, SiBo, LFT, WZ, JZ, SBS, GS, and LMP contributed to the methods and analysis of the HUNT data. DA, ES, OAA, AR and GS collected and analyzed the DemGene data. KB, AZ, InSk, MW, and HZ collected and analyzed the Gothenburg H70 Birth Cohort Studies and Clinical AD Sweden data. AH contributed to the IGAP and ANMerge data. PP provided ANMerge data. DH provided power estimates. RD, LV, 23andMe Research Team, JMS, LKD, NLP, CAR, IKK, SM, HS, ST, PVJ, JS, SK, LA, PS, InSa, IU, SD, TF, SR, and KS analyzed and provided data. DPW wrote the first draft of the manuscript. All authors critically reviewed the paper.
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Snippet 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...
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...
A genome-wide association study performed in 1,126,563 individuals identifies seven new loci associated with Alzheimer's disease and implicates microglia and...
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SubjectTerms 631/208/205/2138
631/378
Agriculture
Alzheimer Disease - genetics
Alzheimer's disease
Animal Genetics and Genomics
Biomedical and Life Sciences
Biomedicine
Cancer Research
drivers
Gene Function
gene-expression
Genetic aspects
Genetic Predisposition to Disease - genetics
Genetic variation
Genetics & Heredity
Genome-wide association studies
Genome-Wide Association Study
Health aspects
heritability
Human Genetics
Humans
Identification and classification
ld score regression
metaanalysis
Methods
Microglia - cytology
Multifactorial Inheritance - genetics
Neurosciences
Neurovetenskaper
polygenic risk
Polymorphism, Single Nucleotide - genetics
Proteins - metabolism
Proteolysis
Risk factors
rna-seq
Sample Size
signatures
transcriptome
Title A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease
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