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

Author:

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.

Abstract

ABSTRACTLimited 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.

Publisher

Cold Spring Harbor Laboratory

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