Alzheimer’s disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 20501. AD is highly heritable, with twin-based heritability estimates of 60–80%2. Although 1,200 causal loci are predicted to exist for AD3, approximately 80 loci have been associated with AD in two recent studies4,5. Low single-nucleotide polymorphism (SNP)-based heritability estimates have prompted the suggestion that little further common-variant risk remains to be found6. 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.
Forfatter(e)
Emil Uffelmann, Douglas P. Wightman, Shahram Bahrami, Alexey A. Shadrin, Vera Fominykh, Takafumi Ojima, Chenyang Jiang, Christian Benner, Elisa Moreno, Adrian I. Campos, Jesper Q. Thomassen, Emmanuel Minois-Genin, Hei Man Wu, G. Bragi Walters, Richard Sherva, Tian Lin, Xuemin Wang, Julien Bryois, Kristi Krebs, Marijn Schipper, Akira Narita, Alessandro Serretti, Anja H. Simonsen, Anna L. van Seumeren, Anne Corbett, Anne-Brita Knapskog, Annette M. Hartmann, Anouk den Braber, Argonde C. van Harten, Arvid Harder, Arvid Rongve, Bengt O. Madsen, Betty M. Tijms, Bitten Aagaard, Bjørn Lichtwarck, Bjørn-Eivind Kirsebom, Byron Creese, Chandra A. Reynolds, Sara Hägg, Ida K. Karlsson, Christian Erikstrup, Christina Mikkelsen, Clive Ballard, Dag Aarsland, Daichi Shigemizu, Dan Rujescu, Daniel Gudbjartsson, Eivind Aakhus, Erik Sørensen, Eystein Stordal, Flora H. Duits, Frank J. Wolters, Frederic Blanc, Geert Jan Biessels, Geir Selbæk, Geir Bråthen, Gen Tamiya, Gunhild Waldemar, Harro Seelaar, Helga Eyjolfsdottir, Henne Holstege, Henning Bundgaard, Henrik Zetterberg, Henrik Ullum, Ina Giegling, Ingmar Skoog, Ingrid T. Medbøen, Ingvild Saltvedt, Irena Rektorova, J. Michael Gaziano, Jan Haavik, Jens Hjerling-Leffler, Jiao Luo, Jon Snaedal, Everard G. B. Vijverberg, Julia M. Sealock, Kaj Blennow, Kaja Nordengen, Karin Persson, Katja Scheffler, Koichi Matsuda, Kouichi Ozaki, Lasse Pihlstrøm, Lavinia Athanasiu, Lene Pålhaugen, Marc Hulsman, Margda Waern, Maria Averina, Marianne Wettergreen, Marta R. Moksnes, Martijn Huisman, Masayuki Yamamoto, Mathias Toft, Matthew S. Panizzon, Mie Topholm Bruun, Mohsen Ghanbari, Monique Franc, Nancy L. Pedersen, Nathaniel Y. Bell, Niccoló Tesi, Ole B. Pedersen, Oleksandr Frei, Olivier Bousiges, Per Svenningsson, Pieter J. Visser, Qingqin S. Li, Richard Hauger, Rui Zhang, Shinichi Namba, Sigrid B. Sando, Silke Kern, Srdjan Djurovic, Steinunn Thordardottir, Tanya N. Phung, Thomas Truelsen, Thomas Werge, Thomas F. Hansen, Tomoki Kyosaka, Torgeir Engstad, Tormod Fladby, Victoria Merritt, Sverre Bergh, Wiesje M. van der Flier, Rujin Wang, Eli A. Stahl, Basavaraj Hooli, LifeLines Cohort Study, DBDS Genomic consortium, Regeneron Genetics Center, Penn Medicine Biobank, GHS–RGC DiscovEHR collaboration, Mayo Clinic-RGC Project Generation, Colorado Center for Personalized Medicine–RGC Collaboration, UCLA–RGC ATLAS collaboration, INDIANA-CHALASANI, Mount Sinai Million Health Discoveries Program, Estonian Biobank research team, VA Million Veteran Program, Lea K. Davis, Mark W. Logue, Kelli Lehto, Anna Zettergren, Ben M. Brumpton, Jian Zeng, Peter M. Visscher, Paul F. O’Reilly, Anubha Mahajan, Manuel Ferreira, Yukinori Okada, Sven J. van der Lee, Sisse R. Ostrowski, Ruth Frikke-Schmidt, Hreinn Stefansson, Karl Heilbron, Ole A. Andreassen & Danielle Posthuma on behalf of PGC-ALZ