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Background <p>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.</p> Results <p>We identify 13 loci with cross-population associations including known loci at/near <i>CR1</i>, <i>BIN1</i>, <i>TREM2</i>, <i>CD2AP</i>, <i>PTK2B</i>, <i>CLU</i>, <i>SHARPIN</i>, <i>MS4A6A</i>, <i>PICALM</i>, <i>ABCA7</i>, <i>APOE</i>, and two novel loci not previously reported at 11p12 (<i>LRRC4C</i>) and 12q24.13 (<i>LHX5-AS1</i>). We additionally identify three population-specific loci with genome-wide significance at/near <i>PTPRK</i> and <i>GRB14</i> in HIS and <i>KIAA0825</i> 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 (<i>LRRC4C</i>, <i>LHX5-AS1</i>, and <i>PTPRK</i>) and insulin receptor activity regulation (<i>GRB14</i>).</p> Conclusions <p>Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near <i>LRRC4C</i> and <i>LHX5-AS1</i>, 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 <i>SHARPIN</i> locus with only 13.7% of the sample size of the NHW GWAS study (<i>n</i> = 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.</p>

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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

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  • 发表日期：

    2025年7月17日

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

摘要

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.