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
Farid Rajabli, Penelope Benchek, Giuseppe Tosto, Nicholas A. Kushch, Jin Sha, Katrina Bazemore, Congcong Zhu, Wan‐Ping Lee, Jacob Haut, Kara L. Hamilton‐Nelson, Nicholas J. Wheeler, Yi Zhao, John J. Farrell, Michelle Grunin, Yuk Yee Leung, Pavel P. Kuksa, Donghe Li, Eder Lúcio da Fonseca, Jesse Mez, Ellen L. Palmer, Jagan A. Pillai, Richard Sherva, Yeunjoo E. Song, Xiaoling Zhang, Takeshi Ikeuchi, Taha Iqbal, Omkar Pathak, Otto Valladares, Dolly Reyes‐Dumeyer, Amanda B Kuzma, Erin L. Abner, Larry D. Adams, Perrie M. Adams, Alyssa Aguirre, Marilyn Albert, Roger L. Albin, Mariet Allen, Lisa Alvarez, Liana G. Apostolova, Steven E. Arnold, Sanjay Asthana, Craig 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. Benítez, David A. Bennett, John Bertelson, Thomas D. Bird, Deborah Blacker, Bradley F. Boeve, James D. Bowen, Adam L. Boxer, James B. 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-Françoise Chesselet, Nathaniel A. Chin, Helena C. Chui, Jaeyoon Chung, Suzanne Craft, Paul K. Crane, David H. Cribbs, Elizabeth Crocco, Carlos Cruchaga, Michael L. Cuccaro, C. Munro Cullum, Eveleen Darby, Bárbara Davis, Philip L. De Jager, Charles DeCarli, John C. DeToledo, Malcolm Dick, Dennis W. Dickson, Beth A. Dombroski, Rachelle S. Doody, Ranjan Duara, NIlüfer Ertekin-Taner, Denis A. Evans, Kelley Faber, Thomas Fairchild, Kenneth B. Fallon, David W. Fardo, Martin R. Farlow
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.