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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Bibliographic Details
Published in:	Nature genetics Vol. 53; no. 9; pp. 1276 - 1282
Main Authors:	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
Language:	English
Published:	New York Nature Publishing Group US 01.09.2021 Nature Publishing Group
Subjects:	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 Sweden
ISSN:	1061-4036, 1546-1718, 1546-1718
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 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.
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-021-00921-z