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

An Author Correction to this article was published on 20 June 2022

An Author Correction to this article was published on 12 November 2021

This article has been updated

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.

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Fig. 1: A Manhattan plot of the meta-analysis results highlighting 38 loci, including seven previously unidentified regions.

Data availability

Access to raw data can be requested via the Psychiatric Genomics Data Access portal (https://www.med.unc.edu/pgc/shared-methods/open-source-philosophy/), UK Biobank (www.ukbiobank.ac.uk), or 23andMe. Restriction of raw data is to protect the privacy of participants. Summary statistics from IGAP (https://web.pasteur-lille.fr/en/recherche/u744/igap/igap_download.php) and Finngen (https://www.finngen.fi/en/access_results) can be obtained from their respective online portals. Summary statistics from the meta-analysis excluding 23andMe are available at https://ctg.cncr.nl/software/summary_statistics. Access to the full set, including 23andMe results, can be obtained after approval from 23andMe is presented to the corresponding author. Approval can be obtained by completion of a Data Transfer Agreement. The Data Transfer Agreement exists to protect the privacy of 23andMe participants. Please visit https://research.23andme.com/dataset-access/ to initiate a request. Summary statistics of the primary microglia eQTLs are also available from EGA (accession no.: EGAD00001005736). MSigDB gene sets are available online (https://www.gsea-msigdb.org/gsea/msigdb/) and integrated in FUMA (https://fuma.ctglab.nl/).

Code availability

The code used to perform the analyses is available at https://github.com/dwightman/PGC-ALZ2. All software used in the analyses is freely available online.

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Acknowledgements

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), and a European Research Council advanced grant (grant no. ERC-2018-AdG GWAS2FUNC 834057 (to D.P.)). 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.

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D.P. and O.A.A. conceived of the study. D.P.W. performed the meta-analysis and follow-up analyses. I.E.J., J.E.S., D.P. and O.A.A. supervised analyses. I.E.J. and J.E.S. generated the UKB data. S. Bahrami and A.A.S. helped with the study design. A.H.S., C.W., J.B.N., L.G.F., M.E.G., K.H., T.W.M. and M.B.J. contributed to the organization of the HUNT data. B.S.W., A.E.M., O.K.D., G.B., I.B., E.S., S. Børte, L.F.T., W.Z., J.-A.Z., S.B.S., G.S. and L.M.P. contributed to the methods and analysis of the HUNT data. D.A., E.S., O.A.A., A.R. and G.S. collected and analyzed the DemGene data. S.K., K.B., A.Z., I. Skoog, M.W. and H.Z. financed and collected the Gothenburg H70 Birth Cohort Studies and Clinical AD Sweden data, and A.Z. processed and coordinated the analysis. A.H. contributed to the IGAP and ANMerge data. P.P. provided ANMerge data. D.H. provided power estimates. R.D., L.V., the 23andMe Research Team, J.M.S., L.K.D., N.L.P., C.A.R., I.K.K., S.M., H.S., S.T., P.V.J., J.S., L.A., P.S., I. Saltvedt, I.U., S.D., T.F., S.R. and K.S. analyzed and provided data. D.P.W. wrote the first draft of the manuscript. All authors critically reviewed the paper

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Correspondence to Danielle Posthuma.

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Competing interests

H.Z. has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx; has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). K.B. has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics and Siemens Healthineers and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. O.A.A. is a consultant to HealthLytix and received speaker’s honorarium from Lundbeck and Sunovion. J.B.N. is employed by Regeneron Pharmaceuticals, Inc. T.W.M. has received speaker’s honorarium from Roche. All other authors declare no competing interests.

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Wightman, D.P., Jansen, I.E., Savage, J.E. et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat Genet 53, 1276–1282 (2021). https://doi.org/10.1038/s41588-021-00921-z

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