Alzheimer’s disease genetics converges on microglial and neuronal dysregulation
Open accessAbstract
. Here we analysed data from 109,479 cases, 74,141 proxy cases, 2,131,799 controls and 499,708 proxy controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and found that genes upregulated in microglia and downregulated in neurons in cases compared with controls were enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a SNP heritability of 16%, nearly threefold higher than previous estimates. Together, our findings show that the common-variant contribution to AD has been substantially underestimated, and reveal new molecular and cellular mechanisms as well as specific targets for future drug development research.
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Cites
Han, B., & Eskin, E. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.04.014 · Cited by 680 · see citing works
Fine-mapping from summary data with the “Sum of Single Effects” model
Zou, Y., Carbonetto, P., Wang, G., & Stephens, M. (2022) · PLOS Genetics · doi:10.1371/journal.pgen.1010299 · Cited by 429 · see citing works
Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation
Srinivasan, K., Friedman, B. A., Etxeberria, A., Huntley, M. A., van der Brug, M. P., Foreman, O., Paw, J. S., Modrusan, Z., Beach, T. G., Serrano, G. E., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107843 · Cited by 427 · see citing works
RICOPILI: Rapid Imputation for COnsortias PIpeLIne
Lam, M., Awasthi, S., Watson, H. J., Goldstein, J., Panagiotaropoulou, G., Trubetskoy, V., Karlsson, R., Frei, O., Fan, C.-C., De Witte, W., et al. (2020) · Bioinformatics · doi:10.1093/bioinformatics/btz633 · Cited by 315 · see citing works
Lopes, K. D. P., Snijders, G. J. L., Humphrey, J., Allan, A., Sneeboer, M. A. M., Navarro, E., Schilder, B. M., Vialle, R. A., Parks, M., Missall, R., et al. (2022) · Nature Genetics · doi:10.1038/s41588-021-00976-y · Cited by 273 · see citing works
Risk prediction of late-onset Alzheimer’s disease implies an oligogenic architecture
Zhang, Q., Sidorenko, J., Couvy-Duchesne, B., Marioni, R. E., Wright, M. J., Goate, A. M., Marcora, E., Huang, K.-L., Porter, T., Laws, S. M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18534-1 · Cited by 272 · see citing works
Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial
Lawlor, B., Segurado, R., Kennelly, S., Olde Rikkert, M. G. M., Howard, R., Pasquier, F., Börjesson-Hanson, A., Tsolaki, M., Lucca, U., Molloy, D. W., et al. (2018) · PLOS Medicine · doi:10.1371/journal.pmed.1002660 · Cited by 193 · see citing works
The role of myelin damage in Alzheimer’s disease pathology
Papuć, E., & Rejdak, K. (2020) · Archives of Medical Science · doi:10.5114/aoms.2018.76863 · Cited by 188 · see citing works
Genetics of the human microglia regulome refines Alzheimer’s disease risk loci
Kosoy, R., Fullard, J. F., Zeng, B., Bendl, J., Dong, P., Rahman, S., Kleopoulos, S. P., Shao, Z., Girdhar, K., Humphrey, J., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01149-1 · Cited by 168 · see citing works
TREM2 promotes Aβ phagocytosis by upregulating C/EBPα-dependent CD36 expression in microglia
Kim, S.-M., Mun, B.-R., Lee, S.-J., Joh, Y., Lee, H.-Y., Ji, K.-Y., Choi, H.-R., Lee, E.-H., Kim, E.-M., Jang, J.-H., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-11634-x · Cited by 143 · see citing works
Including known covariates can reduce power to detect genetic effects in case-control studies
Pirinen, M., Donnelly, P., & Spencer, C. C. A. (2012) · Nature Genetics · doi:10.1038/ng.2346 · Cited by 117 · see citing works
Sex differences in brain protein expression and disease
Wingo, A. P., Liu, Y., Gerasimov, E. S., Vattathil, S. M., Liu, J., Cutler, D. J., Epstein, M. P., Blokland, G. A. M., Thambisetty, M., Troncoso, J. C., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02509-y · Cited by 94 · see citing works
Peyrot, W. J., Boomsma, D. I., Penninx, B. W. J. H., & Wray, N. R. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2015.12.017 · Cited by 42 · see citing works
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- Uffelmann, E., Wightman, D. P., Bahrami, S., Shadrin, A. A., Fominykh, V., Ojima, T., Jiang, C., Benner, C., Moreno, E., Campos, A. I., Thomassen, J. Q., Minois-Genin, E., Wu, H. M., Walters, G. B., Sherva, R., Lin, T., Wang, X., Bryois, J., Krebs, K., Schipper, M., Narita, A., Serretti, A., Simonsen, A. H., van Seumeren, A. L., Corbett, A., Knapskog, A.-B., Hartmann, A. M., den Braber, A., van Harten, A. C., Harder, A., Rongve, A., Madsen, B. O., Tijms, B. M., Aagaard, B., Lichtwarck, B., Kirsebom, B.-E., Creese, B., Reynolds, C. A., Hägg, S., Karlsson, I. K., Erikstrup, C., Mikkelsen, C., Ballard, C., Aarsland, D., Shigemizu, D., Rujescu, D., Gudbjartsson, D., Aakhus, E., Sørensen, E., Stordal, E., Duits, F. H., Wolters, F. J., Blanc, F., Biessels, G. J., Selbæk, G., Bråthen, G., Tamiya, G., Waldemar, G., Seelaar, H., Eyjolfsdottir, H., Holstege, H., Bundgaard, H., Zetterberg, H., Ullum, H., Giegling, I., Skoog, I., Medbøen, I. T., Saltvedt, I., Rektorova, I., Gaziano, J. M., Haavik, J., Hjerling-Leffler, J., Luo, J., Snaedal, J., Vijverberg, E. G. B., Sealock, J. M., Blennow, K., Nordengen, K., Persson, K., Scheffler, K., Matsuda, K., Ozaki, K., Pihlstrøm, L., Athanasiu, L., Pålhaugen, L., Hulsman, M., Waern, M., Averina, M., Wettergreen, M., Moksnes, M. R., Huisman, M., Yamamoto, M., Toft, M., Panizzon, M. S., Topholm Bruun, M., Ghanbari, M., Franc, M., Pedersen, N. L., Bell, N. Y., Tesi, N., Pedersen, O. B., Frei, O., Bousiges, O., Svenningsson, P., Visser, P. J., Li, Q. S., Hauger, R., Zhang, R., Namba, S., Sando, S. B., Kern, S., Djurovic, S., Thordardottir, S., Phung, T. N., Truelsen, T., Werge, T., Hansen, T. F., Kyosaka, T., Engstad, T., Fladby, T., Merritt, V., Bergh, S., van der Flier, W. M., Wang, R., Stahl, E. A., Hooli, B., Study, L. C., DBDS Genomic consortium, Regeneron Genetics Center, Biobank, P. M., Rader, D. J., Ritchie, M. D., Weaver, J., Naseer, N., Sirugo, G., Poindexter, A., Ko, Y.-A., Nerz, K. P., Dever, J., Harvey, A., Linn, S., Livingstone, M., Vadivieso, F., DerOhannessian, S., Tran, T., Stephanowski, J., Santos, S., Haubein, N., Dunn, J., Verma, A., Kripke, C. M., Risman, M., Judy, R., Wollack, C., Verma, S. S., Damrauer, S., Bradford, Y., Dudek, S., Drivas, T., GHS–RGC DiscovEHR collaboration, Buchanan, A., Carey, D. J., Martin, C. L., Meyer, M. N., Retterer, K., Rolston, D., Mayo Clinic-RGC Project Generation, Cerhan, J. R., Couch, F. J., Olson, J. E., Larson, N. B., Fredericksen, Z. S., Cicek, M., Biernacka, J. M., Karpyak, V. M., Vemuri, P., Ramanan, V. K., Frye, M. A., McLaughlin, S. A., Ruddy, K. J., Bielinski, S. J., Lieske, J. C., Hooten, W. M., Boardman, L. A., Kennedy, R. B., Badley, A. D., Dowdy, S. C., Bakkum-Gamez, J. N., Glaser, G. E., Yang, P., Vachon, C. M., Dispenzieri, A., Antwi, S. O., Oberg, A. L., Rabe, K. G., Kaufmann, S. H., Goode, E. L., Cliby, W. A., Ahlskog, J. E., Bower, J. H., Harris, P. C., Pereira, N. L., Ma, D. J., Mutter, R. W., Eckel-Passow, J. E., Colborn, L. K., Danielsen, A. J., Harrington, J. J., Kushwaha, J. M., Colorado Center for Personalized Medicine–RGC Collaboration, Anderson, H. D., Aquilante, C. L., Arbogast, K., Brooks, I. M., Burke, E. E., Casteel, E. M., Cole, J. B., Coughlin, C. R., Crawford, J., Crooks, K., Culver, E., Fisher, M. J., Frye, T. C., George, H., Gignoux, C. R., Gilliland, E. K., Greene, C. S., Hearst, E., Hendricks, A. E., Johnson, R. K., Jones, S., Kao, D., Knortz, G. A., Koffenberger, D., Krishnamoorthy, S., Ku, L., Kudron, E. L., Lacy, R., Lange, E. M., Lesny, J. A., Lin, M., Martin, J. L., UCLA–RGC ATLAS collaboration, Alam, S., Ariannejad, M., Berkovich, Y., Boutros, P., Broudy, M., Bui, A., Chang, T., Denny, C., Dry, S., Duntugan, A., Geschwind, D., Haas, R., Illiev, L., Jain, A., Lajonchere, C., Magyar, C., Martinez, D., Mohammed, G., Naeim, A., Nelson, S., Pasaniuc, B., Patel, Y., Petruse, A., Spellman, P., Tung, P., Yamaguchi, T., INDIANA-CHALASANI, Chalasani, N., Schwantes-An, T.-H. L., Saykin, A. J., Program, M. S. M. H. D., Charney, A. W., Estonian Biobank research team, Program, V. M. V., Davis, L. K., Logue, M. W., Lehto, K., Zettergren, A., Brumpton, B. M., Zeng, J., Visscher, P. M., O’Reilly, P. F., Mahajan, A., Ferreira, M., Okada, Y., van der Lee, S. J., Ostrowski, S. R., Frikke-Schmidt, R., Stefansson, H., Heilbron, K., Andreassen, O. A., Posthuma, D., & PGC-ALZ, O. B. O.
- Affiliations
- Amsterdam Neuroscience (NL)
- Oslo University Hospital (NO)
- Tohoku University (JP)
- Genentech (US)
- Norwegian University of Science and Technology (NO)
- Copenhagen University Hospital (DK)
- Icahn School of Medicine at Mount Sinai (US)
- deCODE Genetics (Iceland) (IS)
- Boston University (US)
- The University of Queensland (AU)
- F. Hoffmann-La Roche AG (CH)
- University of Tartu (EE)
- Università degli Studi di Enna Kore (IT)
- University of Exeter (GB)
- Medical University of Vienna (AT)
- Karolinska Institutet (SE)
- Fonna Hospital Trust (NO)
- Sørlandet Hospital Arendal (NO)
- Aalborg University Hospital (DK)
- Innlandet Hospital Trust (NO)
- University Hospital of North Norway (NO)
- Brunel University of London (GB)
- University of Colorado Boulder (US)
- Aarhus University (DK)
- King's College London (GB)
- Hiroshima University (JP)
- Sykehuset i Vestfold (NO)
- Namsos Hospital (NO)
- Hôpitaux Universitaires de Strasbourg (FR)
- University Medical Center Utrecht (NL)
- University of Copenhagen (DK)
- Erasmus MC (NL)
- University of Iceland (IS)
- University of Gothenburg (SE)
- Statens Serum Institut (DK)
- Sahlgrenska University Hospital (SE)
- Brigham and Women's Hospital (US)
- Haukeland University Hospital (NO)
- Broad Institute (US)
- The University of Tokyo (JP)
- University of Oslo (NO)
- Vrije Universiteit Amsterdam (NL)
- Akershus University Hospital (NO)
- University of California San Diego (US)
- VA Boston Healthcare System (US)
- RIKEN Center for Integrative Medical Sciences (JP)
- Roskilde University (DK)
- Glostrup Hospital (DK)
- Regeneron (United States) (US)
- Eli Lilly (United States) (US)
- New York Genome Center (US)
- ORCID
- Uffelmann, Emil
- Wightman, Douglas P.
- Bahrami, Shahram
- Shadrin, Alexey A.
- Ojima, Takafumi
- Jiang, Chenyang
- Benner, Christian
- Campos, Adrian I.
- Thomassen, Jesper Q.
- Minois-Genin, Emmanuel
- Wu, Hei Man
- Walters, G. Bragi
- Sherva, Richard
- Lin, Tian
- Bryois, Julien
- Krebs, Kristi
- Schipper, Marijn
- Narita, Akira
- Simonsen, Anja H.
- Knapskog, Anne-Brita
- Harder, Arvid
- Rongve, Arvid
- Tijms, Betty M.
- Aagaard, Bitten
- Lichtwarck, Bjørn
- Kirsebom, Bjørn-Eivind
- Creese, Byron
- Reynolds, Chandra A.
- Hägg, Sara
- Karlsson, Ida K.
- Erikstrup, Christian
- Mikkelsen, Christina
- Aarsland, Dag
- Shigemizu, Daichi
- Rujescu, Dan
- Gudbjartsson, Daniel
- Aakhus, Eivind
- Sørensen, Erik
- Stordal, Eystein
- Duits, Flora H.
- Biessels, Geert Jan
- Selbæk, Geir
- Bråthen, Geir
- Tamiya, Gen
- Waldemar, Gunhild
- Seelaar, Harro
- Eyjolfsdottir, Helga
- Holstege, Henne
- Bundgaard, Henning
- Zetterberg, Henrik
- Ullum, Henrik
- Skoog, Ingmar
- Medbøen, Ingrid T.
- Saltvedt, Ingvild
- Rektorova, Irena
- Haavik, Jan
- Hjerling-Leffler, Jens
- Vijverberg, Everard G. B.
- Sealock, Julia M.
- Blennow, Kaj
- Nordengen, Kaja
- Persson, Karin
- Scheffler, Katja
- Matsuda, Koichi
- Ozaki, Kouichi
- Pihlstrøm, Lasse
- Athanasiu, Lavinia
- Pålhaugen, Lene
- Hulsman, Marc
- Waern, Margda
- Averina, Maria
- Moksnes, Marta R.
- Huisman, Martijn
- Yamamoto, Masayuki
- Toft, Mathias
- Panizzon, Matthew S.
- Topholm Bruun, Mie
- Ghanbari, Mohsen
- Pedersen, Nancy L.
- Bell, Nathaniel Y.
- Tesi, Niccoló
- Pedersen, Ole B.
- Frei, Oleksandr
- Bousiges, Olivier
- Svenningsson, Per
- Visser, Pieter J.
- Li, Qingqin S.
- Namba, Shinichi
- Sando, Sigrid B.
- Kern, Silke
- Djurovic, Srdjan
- Phung, Tanya N.
- Werge, Thomas
- Hansen, Thomas F.
- Kyosaka, Tomoki
- Fladby, Tormod
- Bergh, Sverre
- van der Flier, Wiesje M.
- Stahl, Eli A.
- Hooli, Basavaraj
- Rader, Daniel J.
- Weaver, JoEllen
- Naseer, Nawar
- Sirugo, Giorgio
- Ko, Yi-An
- Harvey, Aidan
- Verma, Anurag
- Kripke, Colleen Morse
- Judy, Renae
- Verma, Shefali S.
- Damrauer, Scott
- Dudek, Scott
- Drivas, Theodore
- Carey, David J.
- Martin, Christa L.
- Meyer, Michelle N.
- Retterer, Kyle
- Rolston, David
- Cerhan, James R.
- Olson, Janet E.
- Larson, Nicholas B.
- Biernacka, Joanna M.
- Karpyak, Victor M.
- Vemuri, Prashanthi
- Ramanan, Vijay K.
- Frye, Mark A.
- Bielinski, Suzette J.
- Lieske, John C.
- Hooten, W. Michael
- Kennedy, Richard B.
- Badley, Andrew D.
- Bakkum-Gamez, Jamie N.
- Glaser, Gretchen E.
- Dispenzieri, Angela
- Antwi, Samuel O.
- Oberg, Ann L.
- Rabe, Kari G.
- Kaufmann, Scott H.
- Goode, Ellen L.
- Cliby, William A.
- Ahlskog, J. Eric
- Bower, James H.
- Harris, Peter C.
- Pereira, Naveen L.
- Mutter, Robert W.
- Harrington, Jonathan J.
- Anderson, Heather D.
- Aquilante, Christina L.
- Brooks, Ian M.
- Cole, Joanne B.
- Coughlin, Curtis R.
- Crooks, Kristy
- Greene, Casey S.
- Hendricks, Audrey E.
- Johnson, Randi K.
- Kudron, Elizabeth L.
- Lange, Ethan M.
- Martin, James L.
- Ariannejad, Maryam
- Haas, Roni
- Jain, Ankur
- Lajonchere, Clara
- Naeim, Arash
- Patel, Yash
- Petruse, Antonia
- Saykin, Andrew J.
- Charney, Alexander W.
- Davis, Lea K.
- Logue, Mark W.
- Lehto, Kelli
- Zettergren, Anna
- Brumpton, Ben M.
- Zeng, Jian
- Visscher, Peter M.
- O’Reilly, Paul F.
- Mahajan, Anubha
- Ferreira, Manuel
- Okada, Yukinori
- van der Lee, Sven J.
- Ostrowski, Sisse R.
- Frikke-Schmidt, Ruth
- Stefansson, Hreinn
- Heilbron, Karl
- Andreassen, Ole A.
- Posthuma, Danielle
- Venue
- Nature
- Published
- 2026-10-28
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W7224127212
- Cited by
- 0
- References
- 13
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, genetic risk factors, microglia, neuronal dysfunction, neuroinflammation
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