Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer’s disease

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer’s disease

Abstract Background Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer’s D...

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Main Authors: Farid Rajabli, Penelope Benchek, Giuseppe Tosto, Nicholas Kushch, Jin Sha, Katrina Bazemore, Congcong Zhu, Wan-Ping Lee, Jacob Haut, Kara L. Hamilton-Nelson, Nicholas R. Wheeler, Yi Zhao, John J. Farrell, Michelle A. Grunin, Yuk Yee Leung, Pavel P. Kuksa, Donghe Li, Eder Lucio da Fonseca, Jesse B. Mez, Ellen L. Palmer, Jagan Pillai, Richard M. Sherva, Yeunjoo E. Song, Xiaoling Zhang, Takeshi Ikeuchi, Taha Iqbal, Omkar Pathak, Otto Valladares, Dolly Reyes-Dumeyer, Amanda B. Kuzma, Erin Abner, Larry D. Adams, Perrie M. Adams, Alyssa Aguirre, Marilyn S. Albert, Roger L. Albin, Mariet Allen, Lisa Alvarez, Liana G. Apostolova, Steven E. Arnold, Sanjay Asthana, Craig S. Atwood, Sanford Auerbach, Gayle Ayres, Clinton T. Baldwin, Robert C. Barber, Lisa L. Barnes, Sandra Barral, Thomas G. Beach, James T. Becker, Gary W. Beecham, Duane Beekly, Bruno A. Benitez, David Bennett, John Bertelson, Thomas D. Bird, Deborah Blacker, Bradley F. Boeve, James D. Bowen, Adam Boxer, James Brewer, James R. Burke, Jeffrey M. Burns, Joseph D. Buxbaum, Nigel J. Cairns, Laura B. Cantwell, Chuanhai Cao, Christopher S. Carlson, Cynthia M. Carlsson, Regina M. Carney, Minerva M. Carrasquillo, Scott Chasse, Marie-Francoise Chesselet, Nathaniel A. Chin, Helena C. Chui, Jaeyoon Chung, Suzanne Craft, Paul K. Crane, David H. Cribbs, Elizabeth A. Crocco, Carlos Cruchaga, Michael L. Cuccaro, Munro Cullum, Eveleen Darby, Barbara Davis, Philip L. De Jager, Charles DeCarli, John DeToledo, Malcolm Dick, Dennis W. Dickson, Beth A. Dombroski, Rachelle S. Doody, Ranjan Duara, NIlüfer Ertekin-Taner, Denis A. Evans, Kelley M. Faber, Thomas J. Fairchild, Kenneth B. Fallon, David W. Fardo, Martin R. Farlow, Victoria Fernandez-Hernandez, Steven Ferris, Robert P. Friedland, Tatiana M. Foroud, Matthew P. Frosch, Brian Fulton-Howard, Douglas R. Galasko, Adriana Gamboa, Marla Gearing, Daniel H. Geschwind, Bernardino Ghetti, John R. Gilbert, Rodney C.P. Go, Alison M. Goate, Thomas J. Grabowski, Neill R. Graff-Radford, Robert C. Green, John H. Growdon, Hakon Hakonarson, James Hall, Ronald L. Hamilton, Oscar Harari, John Hardy, Lindy E. Harrell, Elizabeth Head, Victor W. Henderson, Michelle Hernandez, Timothy Hohman, Lawrence S. Honig, Ryan M. Huebinger, Matthew J. Huentelman, Christine M. Hulette, Bradley T. Hyman, Linda S. Hynan, Laura Ibanez, Gail P. Jarvik, Suman Jayadev, Lee-Way Jin, Kim Johnson, Leigh Johnson, M. Ilyas Kamboh, Anna M. Karydas, Mindy J. Katz, John S. Kauwe, Jeffrey A. Kaye, C. Dirk Keene, Aisha Khaleeq, Masataka Kikuchi, Ronald Kim, Janice Knebl, Neil W. Kowall, Joel H. Kramer, Walter A. Kukull, Frank M. LaFerla, James J. Lah, Eric B. Larson, Alan Lerner, James B. Leverenz, Allan I. Levey, Andrew P. Lieberman, Richard B. Lipton, Mark Logue, Oscar L. Lopez, Kathryn L. Lunetta, Constantine G. Lyketsos, Douglas Mains, Flanagan E. Margaret, Daniel C. Marson, Eden RR. Martin, Frank Martiniuk, Deborah C. Mash, Eliezer Masliah, Paul Massman, Arjun Masurkar, Wayne C. McCormick, Susan M. McCurry, Andrew N. McDavid, Stefan McDonough, Ann C. McKee, Marsel Mesulam, Bruce L. Miller, Carol A. Miller, Joshua W. Miller, Thomas J. Montine, Edwin S. Monuki, John C. Morris, Shubhabrata Mukherjee, Amanda J. Myers, Trung Nguyen, Thomas Obisesan, Sid O’Bryant, John M. Olichney, Marcia Ory, Raymond Palmer, Joseph E. Parisi, Henry L. Paulson, Valory Pavlik, David Paydarfar, Victoria Perez, Elaine Peskind, Ronald C. Petersen, Helen Petrovitch, Aimee Pierce, Marsha Polk, Wayne W. Poon, Huntington Potter, Liming Qu, Mary Quiceno, Joseph F. Quinn, Ashok Raj, Murray Raskind, Eric M. Reiman, Barry Reisberg, Joan S. Reisch, John M. Ringman, Erik D. Roberson, Monica Rodriguear, Ekaterina Rogaeva, Howard J. Rosen, Roger N. Rosenberg, Donald R. Royall, Marwan Sabbagh, A. Dessa Sadovnick, Mark A. Sager, Mary Sano, Andrew J. Saykin, Julie A. Schneider, Lon S. Schneider, William W. Seeley, Susan H. Slifer, Scott Small, Amanda G. Smith, Janet P. Smith, Joshua A. Sonnen, Salvatore Spina, Peter St George-Hyslop, Takiyah D. Starks, Robert A. Stern, Alan B. Stevens, Stephen M. Strittmatter, David Sultzer, Russell H. Swerdlow, Rudolph E. Tanzi, Jeffrey L. Tilson, John Q. Trojanowski, Juan C. Troncoso, Magda Tsolaki, Debby W. Tsuang, Vivianna M. Van Deerlin, Linda J. van Eldik, Jeffery M. Vance, Badri N. Vardarajan, Robert Vassar, Harry V. Vinters, Jean-Paul Vonsattel, Sandra Weintraub, Kathleen A. Welsh-Bohmer, Patrice L. Whitehead, Ellen M. Wijsman, Kirk C. Wilhelmsen, Benjamin Williams, Jennifer Williamson, Henrik Wilms, Thomas S. Wingo, Thomas Wisniewski, Randall L. Woltjer, Martin Woon, Clinton B. Wright, Chuang-Kuo Wu, Steven G. Younkin, Chang-En Yu, Lei Yu, Xiongwei Zhu, Brian W. Kunkle, William S. Bush, Akinori Miyashita, Goldie S. Byrd, Li-San Wang, Lindsay A. Farrer, Jonathan L. Haines, Richard Mayeux, Margaret A. Pericak-Vance, Gerard D. Schellenberg, Gyungah R. Jun, Christiane Reitz, Adam C. Naj, on behalf of Alzheimer’s Disease Genetics Consortium (ADGC)
Format: Article
Language:English
Published: BMC 2025-07-01
Series:Genome Biology
Subjects:
Genome-wide association study (GWAS)
GWAS meta-analysis,
Alzheimer disease
Multi-ancestry
Population-specific
Online Access:https://doi.org/10.1186/s13059-025-03564-z
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Summary:Abstract Background Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer’s Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer’s disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. Results We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). Conclusions Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer’s disease.
ISSN:1474-760X

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