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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.

Publication ,  Journal Article
Rajabli, F; Benchek, P; Tosto, G; Kushch, N; Sha, J; Bazemore, K; Zhu, C; Lee, W-P; Haut, J; Hamilton-Nelson, KL; Wheeler, NR; Zhao, Y; Li, D ...
Published in: Genome Biol
July 17, 2025

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.

Duke Scholars

Published In

Genome Biol

DOI

EISSN

1474-760X

Publication Date

July 17, 2025

Volume

26

Issue

1

Start / End Page

210

Location

England

Related Subject Headings

  • White
  • Polymorphism, Single Nucleotide
  • Male
  • Humans
  • Hispanic or Latino
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Genetic Loci
  • Black or African American
  • Bioinformatics
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Rajabli, F., Benchek, P., Tosto, G., Kushch, N., Sha, J., Bazemore, K., … Alzheimer’s Disease Genetics Consortium (ADGC). (2025). 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. Genome Biol, 26(1), 210. https://doi.org/10.1186/s13059-025-03564-z
Rajabli, Farid, Penelope Benchek, Giuseppe Tosto, Nicholas Kushch, Jin Sha, Katrina Bazemore, Congcong Zhu, et al. “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.Genome Biol 26, no. 1 (July 17, 2025): 210. https://doi.org/10.1186/s13059-025-03564-z.
Rajabli F, Benchek P, Tosto G, Kushch N, Sha J, Bazemore K, Zhu C, Lee W-P, Haut J, Hamilton-Nelson KL, Wheeler NR, Zhao Y, Farrell JJ, Grunin MA, Leung YY, Kuksa PP, Li D, da Fonseca EL, Mez JB, Palmer EL, Pillai J, Sherva RM, Song YE, Zhang X, Ikeuchi T, Iqbal T, Pathak O, Valladares O, Reyes-Dumeyer D, Kuzma AB, Abner E, Adams LD, Adams PM, Aguirre A, Albert MS, Albin RL, Allen M, Alvarez L, Apostolova LG, Arnold SE, Asthana S, Atwood CS, Auerbach S, 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 M-F, 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, Friedland RP, Foroud TM, Frosch MP, Fulton-Howard B, Galasko DR, Gamboa A, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Go RCP, 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 L-W, Johnson K, Johnson L, Kamboh MI, Karydas AM, Katz MJ, Kauwe JS, Kaye JA, Keene CD, Khaleeq A, Kikuchi M, 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 ER, 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, Obisesan T, O’Bryant S, Olichney JM, Ory M, Palmer R, Parisi JE, Paulson HL, Pavlik V, Paydarfar D, Perez V, Peskind E, Petersen RC, Petrovitch H, 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, Sabbagh M, Sadovnick AD, Sager MA, Sano M, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Slifer SH, Small S, Smith AG, Smith JP, Sonnen JA, Spina S, George-Hyslop PS, Starks TD, Stern RA, Stevens AB, Strittmatter SM, Sultzer D, Swerdlow RH, Tanzi RE, Tilson JL, Trojanowski JQ, Troncoso JC, Tsolaki M, Tsuang DW, Van Deerlin VM, van Eldik LJ, Vance JM, Vardarajan BN, Vassar R, Vinters HV, Vonsattel J-P, 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 C-K, Younkin SG, Yu C-E, Yu L, Zhu X, Kunkle BW, Bush WS, Miyashita A, Byrd GS, Wang L-S, Farrer LA, Haines JL, Mayeux R, Pericak-Vance MA, Schellenberg GD, Jun GR, Reitz C, Naj AC, Alzheimer’s Disease Genetics Consortium (ADGC). 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. Genome Biol. 2025 Jul 17;26(1):210.

Published In

Genome Biol

DOI

EISSN

1474-760X

Publication Date

July 17, 2025

Volume

26

Issue

1

Start / End Page

210

Location

England

Related Subject Headings

  • White
  • Polymorphism, Single Nucleotide
  • Male
  • Humans
  • Hispanic or Latino
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Genetic Loci
  • Black or African American
  • Bioinformatics