학술논문
Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK , GRB14 , and KIAA0825 as novel risk loci for Alzheimer's disease: the Alzheimer's Disease Genetics Consortium.
Document Type
Author
Rajabli F; Benchek P; Tosto G; Kushch N; Sha J; Bazemore K; Zhu C; Lee WP; Haut J; Hamilton-Nelson KL; Wheeler NR; Zhao Y; Farrell JJ; Grunin MA; Leung YY; Kuksa PP; Li D; Lucio da Fonseca E; Mez JB; Palmer EL; Pillai J; Sherva RM; Song YE; Zhang X; Iqbal T; Pathak O; Valladares O; Kuzma AB; Abner E; Adams PM; Aguirre A; Albert MS; Albin RL; Allen M; Alvarez L; Apostolova LG; Arnold SE; Asthana S; Atwood CS; Ayres G; Baldwin CT; Barber RC; Barnes LL; Barral S; Beach TG; Becker JT; Beecham GW; Beekly D; Benitez BA; Bennett D; Bertelson J; Bird TD; Blacker D; Boeve BF; Bowen JD; Boxer A; Brewer J; Burke JR; Burns JM; Buxbaum JD; Cairns NJ; Cantwell LB; Cao C; Carlson CS; Carlsson CM; Carney RM; Carrasquillo MM; Chasse S; Chesselet MF; Chin NA; Chui HC; Chung J; Craft S; Crane PK; Cribbs DH; Crocco EA; Cruchaga C; Cuccaro ML; Cullum M; Darby E; Davis B; De Jager PL; DeCarli C; DeToledo J; Dick M; Dickson DW; Dombroski BA; Doody RS; Duara R; Ertekin-Taner N; Evans DA; Faber KM; Fairchild TJ; Fallon KB; Fardo DW; Farlow MR; Fernandez-Hernandez V; Ferris S; Foroud TM; Frosch MP; Fulton-Howard B; Galasko DR; Gamboa A; Gearing M; Geschwind DH; Ghetti B; Gilbert JR; Goate AM; Grabowski TJ; Graff-Radford NR; Green RC; Growdon JH; Hakonarson H; Hall J; Hamilton RL; Harari O; Hardy J; Harrell LE; Head E; Henderson VW; Hernandez M; Hohman T; Honig LS; Huebinger RM; Huentelman MJ; Hulette CM; Hyman BT; Hynan LS; Ibanez L; Jarvik GP; Jayadev S; Jin LW; Johnson K; Johnson L; Kamboh MI; Karydas AM; Katz MJ; Kauwe JS; Kaye JA; Keene CD; Khaleeq A; Kim R; Knebl J; Kowall NW; Kramer JH; Kukull WA; LaFerla FM; Lah JJ; Larson EB; Lerner A; Leverenz JB; Levey AI; Lieberman AP; Lipton RB; Logue M; Lopez OL; Lunetta KL; Lyketsos CG; Mains D; Margaret FE; Marson DC; Martin ERR; Martiniuk F; Mash DC; Masliah E; Massman P; Masurkar A; McCormick WC; McCurry SM; McDavid AN; McDonough S; McKee AC; Mesulam M; Miller BL; Miller CA; Miller JW; Montine TJ; Monuki ES; Morris JC; Mukherjee S; Myers AJ; Nguyen T; O'Bryant S; Olichney JM; Ory M; Palmer R; Parisi JE; Paulson HL; Pavlik V; Paydarfar D; Perez V; Peskind E; Petersen RC; Pierce A; Polk M; Poon WW; Potter H; Qu L; Quiceno M; Quinn JF; Raj A; Raskind M; Reiman EM; Reisberg B; Reisch JS; Ringman JM; Roberson ED; Rodriguear M; Rogaeva E; Rosen HJ; Rosenberg RN; Royall DR; Sager MA; Sano M; Saykin AJ; Schneider JA; Schneider LS; Seeley WW; Slifer SH; Small S; Smith AG; Smith JP; Sonnen JA; Spina S; St George-Hyslop P; Stern RA; Stevens AB; Strittmatter SM; Sultzer D; Swerdlow RH; Tanzi RE; Tilson JL; Trojanowski JQ; Troncoso JC; Tsuang DW; Van Deerlin VM; van Eldik LJ; Vance JM; Vardarajan BN; Vassar R; Vinters HV; Vonsattel JP; Weintraub S; Welsh-Bohmer KA; Whitehead PL; Wijsman EM; Wilhelmsen KC; Williams B; Williamson J; Wilms H; Wingo TS; Wisniewski T; Woltjer RL; Woon M; Wright CB; Wu CK; Younkin SG; Yu CE; Yu L; Zhu X; Kunkle BW; Bush WS; Wang LS; Farrer LA; Haines JL; Mayeux R; Pericak-Vance MA; Schellenberg GD; Jun GR; Reitz C; Naj AC
Source
Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE
Subject
Language
English
Abstract
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/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 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus 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 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.