对56241名个体进行的多祖先全基因组荟萃分析确定了已知和新的跨人群及特定祖先关联，作为阿尔茨海默病的新风险位点。
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.
作者信息
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, da Fonseca Eder Lucio, Mez Jesse B, Palmer Ellen L, Pillai Jagan, Sherva Richard M, Song Yeunjoo E, Zhang Xiaoling, Ikeuchi Takeshi, Iqbal Taha, Pathak Omkar, Valladares Otto, Reyes-Dumeyer Dolly, Kuzma Amanda B, Abner Erin, Adams Larry D, 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, Auerbach Sanford, 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, Friedland Robert P, Foroud Tatiana M, Frosch Matthew P, Fulton-Howard Brian, Galasko Douglas R, Gamboa Adriana, Gearing Marla, Geschwind Daniel H, Ghetti Bernardino, Gilbert John R, Go Rodney C P, 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, Kikuchi Masataka, 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 Rr, 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, Obisesan Thomas, 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, Petrovitch Helen, 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, Sabbagh Marwan, Sadovnick A Dessa, 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, George-Hyslop Peter St, Starks Takiyah D, 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, Tsolaki Magda, 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, Miyashita Akinori, Byrd Goldie 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
机构信息
Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA.
The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
出版信息
Genome Biol. 2025 Jul 17;26(1):210. doi: 10.1186/s13059-025-03564-z.
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.
背景
在全基因组关联研究（GWAS）中，有限的祖先多样性削弱了我们检测在主要非欧洲祖先背景的祖先群体中更普遍的风险变异的能力。我们构建并分析了阿尔茨海默病遗传学联盟（ADGC）中的一个多祖先GWAS数据集，以检测新的共享和特定人群的晚发性阿尔茨海默病（LOAD）易感位点，并评估37382名非西班牙裔白人（NHW）、6728名非裔美国人、8899名西班牙裔（HIS）和3232名东亚个体的潜在遗传结构，先进行祖先内固定效应荟萃分析，然后进行跨祖先随机效应荟萃分析。
结果
我们鉴定出13个具有跨人群关联的位点，包括CR1、BIN1、TREM2、CD2AP、PTK2B、CLU、SHARPIN、MS4A6A、PICALM、ABCA7、APOE附近的已知位点，以及11p12（LRRC4C）和12q24.13（LHX5-AS1）处两个先前未报道的新位点。我们还在HIS人群中PTPRK和GRB14附近以及NHW人群中KIAA0825附近鉴定出三个具有全基因组显著性的特定人群位点。通路分析涉及多个淀粉样蛋白调节通路和经典补体通路。我们新位点附近的基因在神经元发育（LRRC4C、LHX5-AS1和PTPRK）和胰岛素受体活性调节（GRB14）中具有已知作用。
结论
通过跨人群GWAS荟萃分析，我们在LRRC4C和LHX5-AS1附近鉴定出了新的LOAD易感位点，这两个位点在神经元发育中均具有已知作用，以及几个新的人群特异性位点。反映了GWAS中不同祖先的强大作用，我们在仅占首次观察到该位点的NHW GWAS研究样本量13.7%（n = 409589）的样本中检测到了SHARPIN位点。继续扩展到更大的多祖先研究将为进一步阐明晚发性阿尔茨海默病的基因组学提供更大的助力。
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