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Novel genetic determinants of telomere length from a multi-ethnic analysis of 75,000 whole genome sequences in TOPMed

By Margaret A Taub, Joshua S Weinstock, Kruthika R Iyer, Lisa R. Yanek, Matthew P Conomos, Jennifer A Brody, Ali Keramati, Cecelia A Laurie, Marios Arvanitis, Albert V Smith, John Lane, Lewis C. Becker, Joshua C Bis, John Blangero, Eugene R Bleecker, Esteban G. Burchard, Juan C. Celedon, 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, Christie Ingram, Marguerite R Irvin, W Craig Johnson, Stefan Kaab, Lenore Launer, Jiwon Lee, Simin Liu, Arden Moscati, Kari E. North, Patricia A. Peyser, Nicholas Rafaels, Laura M Raffield, Daniel E Weeks, Marsha M Wheeler, L. Keoki Williams, Wei Zhao, Mary Armanios, Stella Aslibekyan, Paul L. Auer, Donald W Bowden, Brian E. Cade, Ida Yii-Der Chen, Michael H Cho, L. Adrienne Cupples, Joanne E. Curran, Michelle Daya, Ranjan Deka, Xiuqing Guo, Lifang Hou, Shih-Jen Hwang, Jill M Johnsen, Eimear E Kenny, Albert M Levin, Chunyu Liu, Ryan L. Minster, Mehdi Nouraie, Ester C Sabino, Jennifer A. Smith, Nicholas L. Smith, Jessica Lasky Su, 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, Jerome I. Rotter, Susan Redline, Bruce M. Psaty, Juan M. Peralta, Nicholette D Palmer, Ruth J.F. Loos, Courtney G Montgomery, Braxton D Mitchell, Deborah A Meyers, Stephen T McGarvey, Angel C.Y. Mak, Rajesh Kumar, Charles Kooperberg, Barbara A Konkle, Shannon Kelly, Sharon LR Kardia, Robert Kaplan, Jiang He, Hongsheng Gui, Myriam Fornage, Patrick T. Ellinor, Mariza de Andrade, Adolfo Correa, Eric Boerwinkle, Kathleen C Barnes, Allison E Ashley-Koch, Donna K. Arnett, Christine Albert, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group, Cathy C Laurie, Gonçalo R. Abecasis, Abraham Aviv, Deborah A. Nickerson, James G Wilson, Stephen S Rich, Daniel Levy, Alexis Battle, Thomas W Blackwell, Ingo Ruczinski, Timothy Thornton, Jeff O’Connell, James A Perry, Nathan Pankratz, Alexander P. Reiner, Rasika A. Mathias

Posted 04 Sep 2019
bioRxiv DOI: 10.1101/749010

Telomeres shorten in replicating somatic cells and with age; in human leukocytes, telomere length (TL) is associated with a host of aging-related diseases. To date, 16 genome-wide association studies (GWAS) have identified twenty-three loci associated with leukocyte TL, but prior studies were primarily in individuals of European and Asian ancestry and relied on laboratory assays including Southern Blot and qPCR to quantify TL. Here, we estimated TL bioinformatically, leveraging whole genome sequencing (WGS) of whole blood from n=75,176 subjects in the Trans-Omics for Precision Medicine (TOPMed) Program. We performed the largest multi-ethnic and only WGS-based genome-wide association analysis of TL to date. We identified 22 associated loci (p-value <5x10-8), including 10 novel loci. Three of the novel loci map to genes involved in telomere maintenance and/or DNA damage repair: TERF2, RFWD3, and SAMHD1. Many of the 99 pathways identified in gene set enrichment analysis for the 22 loci (multiple-testing corrected false discovery rate (FDR) <0.05) pertain to telomere biology, including the top five (FDR<1x10-9). Importantly, several loci, including the recently identified TINF2 and ATM loci, showed strong ancestry-specific associations.

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