来自TOPMed中109122个具有不同祖先的全基因组序列的端粒长度的遗传决定因素。
Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed.
作者信息
Taub Margaret A, Conomos Matthew P, Keener Rebecca, Iyer Kruthika R, Weinstock Joshua S, Yanek Lisa R, Lane John, Miller-Fleming Tyne W, Brody Jennifer A, Raffield Laura M, McHugh Caitlin P, Jain Deepti, Gogarten Stephanie M, Laurie Cecelia A, Keramati Ali, Arvanitis Marios, Smith Albert V, Heavner Benjamin, Barwick Lucas, Becker Lewis C, Bis Joshua C, Blangero John, Bleecker Eugene R, Burchard Esteban G, Celedón Juan C, Chang Yen Pei C, Custer Brian, Darbar Dawood, de las Fuentes Lisa, DeMeo Dawn L, Freedman Barry I, Garrett Melanie E, Gladwin Mark T, Heckbert Susan R, Hidalgo Bertha A, Irvin Marguerite R, Islam Talat, Johnson W Craig, Kaab Stefan, Launer Lenore, Lee Jiwon, Liu Simin, Moscati Arden, North Kari E, Peyser Patricia A, Rafaels Nicholas, Seidman Christine, Weeks Daniel E, Wen Fayun, Wheeler Marsha M, Williams L Keoki, Yang Ivana V, Zhao Wei, Aslibekyan Stella, Auer Paul L, Bowden Donald W, Cade Brian E, Chen Zhanghua, Cho Michael H, Cupples L Adrienne, Curran Joanne E, Daya Michelle, Deka Ranjan, Eng Celeste, Fingerlin Tasha E, Guo Xiuqing, Hou Lifang, Hwang Shih-Jen, Johnsen Jill M, Kenny Eimear E, Levin Albert M, Liu Chunyu, Minster Ryan L, Naseri Take, Nouraie Mehdi, Reupena Muagututi'a Sefuiva, Sabino Ester C, Smith Jennifer A, Smith Nicholas L, Su Jessica Lasky, Taylor James G, Telen Marilyn J, Tiwari Hemant K, Tracy Russell P, White Marquitta J, Zhang Yingze, Wiggins Kerri L, Weiss Scott T, Vasan Ramachandran S, Taylor Kent D, Sinner Moritz F, Silverman Edwin K, Shoemaker M Benjamin, Sheu Wayne H-H, Sciurba Frank, Schwartz David A, Rotter Jerome I, Roden Daniel, Redline Susan, Raby Benjamin A, Psaty Bruce M, Peralta Juan M, Palmer Nicholette D, Nekhai Sergei, Montgomery Courtney G, Mitchell Braxton D, Meyers Deborah A, McGarvey Stephen T, Mak Angel Cy, Loos Ruth Jf, Kumar Rajesh, Kooperberg Charles, Konkle Barbara A, Kelly Shannon, Kardia Sharon Lr, Kaplan Robert, He Jiang, Gui Hongsheng, Gilliland Frank D, Gelb Bruce D, Fornage Myriam, Ellinor Patrick T, de Andrade Mariza, Correa Adolfo, Chen Yii-Der Ida, Boerwinkle Eric, Barnes Kathleen C, Ashley-Koch Allison E, Arnett Donna K, Laurie Cathy C, Abecasis Goncalo, Nickerson Deborah A, Wilson James G, Rich Stephen S, Levy Daniel, Ruczinski Ingo, Aviv Abraham, Blackwell Thomas W, Thornton Timothy, O'Connell Jeff, Cox Nancy J, Perry James A, Armanios Mary, Battle Alexis, Pankratz Nathan, Reiner Alexander P, Mathias Rasika A
机构信息
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA.
Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
出版信息
Cell Genom. 2022 Jan 12;2(1). doi: 10.1016/j.xgen.2021.100084. Epub 2022 Jan 13.
Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value <5×10) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at indicated the independent signals colocalized with cell-type specific eQTLs for (). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, () and . In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes.
端粒长度的遗传学研究对于理解与年龄相关的疾病至关重要。先前针对白细胞端粒长度的全基因组关联研究（GWAS）仅限于欧洲和亚洲人群。在此，我们报告了第一项基于测序的端粒长度关联研究，该研究涉及美国国立心肺血液研究所（NHLBI）精准医学跨组学（TOPMed）计划中来自不同祖先群体（欧洲、非洲、亚洲和西班牙裔/拉丁裔）的个体。我们使用全血的全基因组测序（WGS）进行变异基因型分型，并对n = 109,122名个体的端粒长度进行生物信息学估计。我们在36个与端粒长度相关的基因座中鉴定出59个哨兵变异（p值<5×10），其中包括20个新关联的基因座（13个在外部数据集中得到重复验证）。几乎没有证据表明不同人群之间效应大小存在异质性。精细定位表明，独立信号与（）的细胞类型特异性表达数量性状位点（eQTL）共定位。使用基于多变异基因的方法，我们鉴定出两个新涉及端粒长度的基因，（）和。在表型组关联研究（PheWAS）中，我们证明我们的端粒长度多基因性状评分（PTS）与癌症相关表型的风险增加有关。
Zotero 插件