e-Article
Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed
Document Type
article
Author
Margaret A. Taub; Matthew P. Conomos; Rebecca Keener; Kruthika R. Iyer; Joshua S. Weinstock; Lisa R. Yanek; John Lane; Tyne W. Miller-Fleming; Jennifer A. Brody; Laura M. Raffield; Caitlin P. McHugh; Deepti Jain; Stephanie M. Gogarten; Cecelia A. Laurie; Ali Keramati; Marios Arvanitis; Albert V. Smith; Benjamin Heavner; Lucas Barwick; Lewis C. Becker; Joshua C. Bis; John Blangero; Eugene R. Bleecker; Esteban G. Burchard; Juan C. Celedón; Yen Pei C. Chang; Brian Custer; Dawood Darbar; Lisa de las Fuentes; Dawn L. DeMeo; Barry I. Freedman; Melanie E. Garrett; Mark T. Gladwin; Susan R. Heckbert; Bertha A. Hidalgo; Marguerite R. Irvin; Talat Islam; W. Craig Johnson; Stefan Kaab; Lenore Launer; Jiwon Lee; Simin Liu; Arden Moscati; Kari E. North; Patricia A. Peyser; Nicholas Rafaels; Christine Seidman; Daniel E. Weeks; Fayun Wen; Marsha M. Wheeler; L. Keoki Williams; Ivana V. Yang; Wei Zhao; Stella Aslibekyan; Paul L. Auer; Donald W. Bowden; Brian E. Cade; Zhanghua Chen; Michael H. Cho; L. Adrienne Cupples; Joanne E. Curran; Michelle Daya; Ranjan Deka; Celeste Eng; Tasha E. Fingerlin; Xiuqing Guo; Lifang Hou; Shih-Jen Hwang; Jill M. Johnsen; Eimear E. Kenny; Albert M. Levin; Chunyu Liu; Ryan L. Minster; Take Naseri; Mehdi Nouraie; Muagututi‘a Sefuiva Reupena; Ester C. Sabino; Jennifer A. Smith; Nicholas L. Smith; Jessica Lasky-Su; James G. Taylor, VI; Marilyn J. Telen; Hemant K. Tiwari; Russell P. Tracy; Marquitta J. White; Yingze Zhang; Kerri L. Wiggins; Scott T. Weiss; Ramachandran S. Vasan; Kent D. Taylor; Moritz F. Sinner; Edwin K. Silverman; M. Benjamin Shoemaker; Wayne H.-H. Sheu; Frank Sciurba; David A. Schwartz; Jerome I. Rotter; Daniel Roden; Susan Redline; Benjamin A. Raby; Bruce M. Psaty; Juan M. Peralta; Nicholette D. Palmer; Sergei Nekhai; Courtney G. Montgomery; Braxton D. Mitchell; Deborah A. Meyers; Stephen T. McGarvey; Angel C.Y. Mak; Ruth J.F. Loos; Rajesh Kumar; Charles Kooperberg; Barbara A. Konkle; Shannon Kelly; Sharon L.R. Kardia; Robert Kaplan; Jiang He; Hongsheng Gui; Frank D. Gilliland; Bruce D. Gelb; Myriam Fornage; Patrick T. Ellinor; Mariza de Andrade; Adolfo Correa; Yii-Der Ida Chen; Eric Boerwinkle; Kathleen C. Barnes; Allison E. Ashley-Koch; Donna K. Arnett; Christine Albert; Cathy C. Laurie; Goncalo Abecasis; Deborah A. Nickerson; James G. Wilson; Stephen S. Rich; Daniel Levy; Ingo Ruczinski; Abraham Aviv; Thomas W. Blackwell; Timothy Thornton; Jeff O’Connell; Nancy J. Cox; James A. Perry; Mary Armanios; Alexis Battle; Nathan Pankratz; Alexander P. Reiner; Rasika A. Mathias
Source
Cell Genomics, Vol 2, Iss 1, Pp 100084- (2022)
Subject
Language
English
ISSN
2666-979X
Abstract
Summary: Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs 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 < 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 that 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 that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.