Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifiesLRRC4C, LHX5-AS1and nominates ancestry-specific lociPTPRK,GRB14, andKIAA0825as novel risk loci for Alzheimer’s disease: the Alzheimer’s Disease Genetics Consortium
Authors: Rajabli Farid , Benchek Penelope , Tosto Giuseppe , Kushch Nicholas , Sha Jin , Bazemore Katrina , Zhu Congcong , Lee Wan-Ping , Haut Jacob , Hamilton-Nelson Kara L. , Wheeler Nicholas R. , Zhao Yi , Farrell John J. , Grunin Michelle A. , Leung Yuk Yee , Kuksa Pavel P. , Li Donghe , Lucio da Fonseca Eder , Mez Jesse B. , Palmer Ellen L. , Pillai Jagan , Sherva Richard M. , Song Yeunjoo E. , Zhang Xiaoling , Iqbal Taha , Pathak Omkar , Valladares Otto , Kuzma Amanda B. , Abner Erin , Adams Perrie M. , Aguirre Alyssa , Albert Marilyn S. , Albin Roger L. , Allen Mariet , Alvarez Lisa , Apostolova Liana G. , Arnold Steven E. , Asthana Sanjay , Atwood Craig S. , Ayres Gayle , Baldwin Clinton T. , Barber Robert C. , Barnes Lisa L. , Barral Sandra , Beach Thomas G. , Becker James T. , Beecham Gary W. , Beekly Duane , Benitez Bruno A. , Bennett David , Bertelson John , Bird Thomas D. , Blacker Deborah , Boeve Bradley F. , Bowen James D. , Boxer Adam , Brewer James , Burke James R. , Burns Jeffrey M. , Buxbaum Joseph D. , Cairns Nigel J. , Cantwell Laura B. , Cao Chuanhai , Carlson Christopher S. , Carlsson Cynthia M. , Carney Regina M. , Carrasquillo Minerva M. , Chasse Scott , Chesselet Marie-Francoise , Chin Nathaniel A. , Chui Helena C. , Chung Jaeyoon , Craft Suzanne , Crane Paul K. , Cribbs David H. , Crocco Elizabeth A. , Cruchaga Carlos , Cuccaro Michael L. , Cullum Munro , Darby Eveleen , Davis Barbara , De Jager Philip L. , DeCarli Charles , DeToledo John , Dick Malcolm , Dickson Dennis W. , Dombroski Beth A. , Doody Rachelle S. , Duara Ranjan , Ertekin-Taner NIlüfer , Evans Denis A. , Faber Kelley M. , Fairchild Thomas J. , Fallon Kenneth B. , Fardo David W. , Farlow Martin R. , Fernandez-Hernandez Victoria , Ferris Steven , Foroud Tatiana M. , Frosch Matthew P. , Fulton-Howard Brian , Galasko Douglas R. , Gamboa Adriana , Gearing Marla , Geschwind Daniel H. , Ghetti Bernardino , Gilbert John R. , Goate Alison M. , Grabowski Thomas J. , Graff-Radford Neill R. , Green Robert C. , Growdon John H. , Hakonarson Hakon , Hall James , Hamilton Ronald L. , Harari Oscar , Hardy John , Harrell Lindy E. , Head Elizabeth , Henderson Victor W. , Hernandez Michelle , Hohman Timothy , Honig Lawrence S. , Huebinger Ryan M. , Huentelman Matthew J. , Hulette Christine M. , Hyman Bradley T. , Hynan Linda S. , Ibanez Laura , Jarvik Gail P. , Jayadev Suman , Jin Lee-Way , Johnson Kim , Johnson Leigh , Kamboh M. Ilyas , Karydas Anna M. , Katz Mindy J. , Kauwe John S. , Kaye Jeffrey A. , Keene C. Dirk , Khaleeq Aisha , Kim Ronald , Knebl Janice , Kowall Neil W. , Kramer Joel H. , Kukull Walter A. , LaFerla Frank M. , Lah James J. , Larson Eric B. , Lerner Alan , Leverenz James B. , Levey Allan I. , Lieberman Andrew P. , Lipton Richard B. , Logue Mark , Lopez Oscar L. , Lunetta Kathryn L. , Lyketsos Constantine G. , Mains Douglas , Margaret Flanagan E. , Marson Daniel C. , Martin Eden R R. , Martiniuk Frank , Mash Deborah C. , Masliah Eliezer , Massman Paul , Masurkar Arjun , McCormick Wayne C. , McCurry Susan M. , McDavid Andrew N. , McDonough Stefan , McKee Ann C. , Mesulam Marsel , Miller Bruce L. , Miller Carol A. , Miller Joshua W. , Montine Thomas J. , Monuki Edwin S. , Morris John C. , Mukherjee Shubhabrata , Myers Amanda J. , Nguyen Trung , O’Bryant Sid , Olichney John M. , Ory Marcia , Palmer Raymond , Parisi Joseph E. , Paulson Henry L. , Pavlik Valory , Paydarfar David , Perez Victoria , Peskind Elaine , Petersen Ronald C. , Pierce Aimee , Polk Marsha , Poon Wayne W. , Potter Huntington , Qu Liming , Quiceno Mary , Quinn Joseph F. , Raj Ashok , Raskind Murray , Reiman Eric M. , Reisberg Barry , Reisch Joan S. , Ringman John M. , Roberson Erik D. , Rodriguear Monica , Rogaeva Ekaterina , Rosen Howard J. , Rosenberg Roger N. , Royall Donald R. , Sager Mark A. , Sano Mary , Saykin Andrew J. , Schneider Julie A. , Schneider Lon S. , Seeley William W. , Slifer Susan H. , Small Scott , Smith Amanda G. , Smith Janet P. , Sonnen Joshua A. , Spina Salvatore , St George-Hyslop Peter , Stern Robert A. , Stevens Alan B. , Strittmatter Stephen M. , Sultzer David , Swerdlow Russell H. , Tanzi Rudolph E. , Tilson Jeffrey L. , Trojanowski John Q. , Troncoso Juan C. , Tsuang Debby W. , Van Deerlin Vivianna M. , van Eldik Linda J. , Vance Jeffery M. , Vardarajan Badri N. , Vassar Robert , Vinters Harry V. , Vonsattel Jean-Paul , Weintraub Sandra , Welsh-Bohmer Kathleen A. , Whitehead Patrice L. , Wijsman Ellen M. , Wilhelmsen Kirk C. , Williams Benjamin , Williamson Jennifer , Wilms Henrik , Wingo Thomas S. , Wisniewski Thomas , Woltjer Randall L. , Woon Martin , Wright Clinton B. , Wu Chuang-Kuo , Younkin Steven G. , Yu Chang-En , Yu Lei , Zhu Xiongwei , Kunkle Brian W. , Bush William S. , Wang Li-San , Farrer Lindsay A. , Haines Jonathan L. , Mayeux Richard , Pericak-Vance Margaret A. , Schellenberg Gerard D. , Jun Gyungah R. , Reitz Christiane , Naj Adam C. 
Published: July 2023

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer’s Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/nearCR1,BIN1,TREM2,CD2AP,PTK2B,CLU,SHARPIN,MS4A6A,PICALM,ABCA7,APOEand two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). Reflecting the power of diverse ancestry in GWAS, we observed theSHARPINlocus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near (PTPRK(P=2.4×10-8) andGRB14(P=1.7×10-8) in HIS), andKIAA0825(P=2.9×10-8in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest withPadjusted=1.6×10-4) and the classical complement pathway (Padjusted=1.3×10-3). Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, andPTPRK) and insulin receptor activity regulation (GRB14). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.