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Cell genomics · 2022

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed.

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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, NHLBI CARE Network, 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, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group, 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

Аннотация

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 <5×10-9) 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 OBFC1 indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes.

ИП Урсолов Владлен Сергеевич

ИНН 500118482352 · ОГРНИП 314500117700049

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