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Novel genetic determinants of telomere length from a trans-ethnic analysis of 109,122 whole genome sequences in TOPMed

By Margaret A Taub, Matthew Conomos, Rebecca LR Keener, Kruthika Iyer, Joshua Weinstock, Lisa Yanek, John D Lane, Tyne Miller-Fleming, Jennifer Brody, Caitlin T McHugh, Deepti Jain, Stephanie Gogarten, Cecelia Ida Laurie, Ali Keramati, Marios C Arvanitis, Albert E Smith, Benjamin K Heavner, Lucas Barwick, Lewis C. Becker, Joshua Bis, John A Blangero, Eugene G Bleecker, Esteban S Burchard, Juan Celedon, Yen Pei Chang, Brian Custer, Dawood W Darbar, Lisa de las Fuentes, Dawn DeMeo, Barry J Freedman, Melanie A Garrett, Mark Gladwin, Susan Heckbert, Bertha Hidalgo, Marguerite P Irvin, Talat A Islam, W Johnson, Stefan Kaab, Lenore Launer, Jiwon Lee, Simin Liu, Arden Moscati, Kari North, Patricia Peyser, Nicholas Rafaels, Laura Raffield, Christine Seidman, Daniel Weeks, Fayun Wen, Marsha Wheeler, L. Keoki Williams, Ivana Yang, Wei Zhao, Stella Aslibekyan, Paul Auer, Donald Bowden, Brian Cade, Zhanghua Chen, Michael Cho, L Cupples, Joanne Curran, Michelle Daya, Ranjan Deka, Celeste Eng, Tasha Fingerlin, Xiuqing Guo, Lifang Hou, Shih-Jen Hwang, Jill Johnsen, Eimear Kenny, Albert Levin, Chunyu Liu, Ryan Minster, Take Naseri, Mehdi Nouraie, Muagututi'a Reupena, Ester Sabino, Jennifer Smith, Nicholas Smith, Jessica Su, James Taylor, Marilyn Telen, Hemant Tiwari, Russell Tracy, Marquitta White, Yingze Zhang, Kerri Wiggins, Scott Weiss, Ramachandran Vasan, Kent Taylor, Moritz Sinner, Edwin Silverman, M. Benjamin Shoemaker, Wayne Sheu, Frank Sciurba, David Schwartz, Jerome Rotter, Daniel Roden, Susan Redline, Benjamin Raby, Bruce Psaty, Juan Peralta, Nicholette Palmer, Sergei Nekhai, Courtney Montgomery, Braxton Mitchell, Deborah Meyers, Stephen McGarvey, Fernando Martinez, Angel Mak, Ruth Loos, Rajesh Kumar, Charles Kooperberg, Barbara Konkle, Shannon Kelly, Sharon Kardia, Robert Kaplan, Jiang He, Hongsheng Gui, Frank Gilliland, Bruce Gelb, Myriam Fornage, Patrick Ellinor, Mariza de Andrade, Adolfo Correa, Yii-Der Chen, Eric Boerwinkle, Kathleen Barnes, Allison Ashley-Koch, Donna Arnett, Christine Albert, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group, Cathy Laurie, Goncalo Abecasis, Deborah Nickerson, James Wilson, Stephen Rich, Daniel Levy, Ingo Ruczinski, Abraham Aviv, Thomas Blackwell, Timothy Thornton, Jeff O'Connell, Nancy Cox, James Perry, Mary Armanios, Alexis Battle, Nathan Pankratz, Alexander Reiner, Rasika Mathias

Posted 04 Sep 2019
bioRxiv DOI: 10.1101/749010

Telomeres shorten in replicating somatic cells, and telomere length (TL) is associated with age-related diseases 1,2. To date, 17 genome-wide association studies (GWAS) have identified 25 loci for leukocyte TL 3-19, but were limited to European and Asian ancestry individuals and relied on laboratory assays of TL. In this study 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 TL in n=109,122 trans-ethnic (European, African, Asian and Hispanic/Latino) individuals. We identified 59 sentinel variants (p-value <5x10-9) from 36 loci (20 novel, 13 replicated in external datasets). There was little evidence of effect heterogeneity across populations, and 10 loci had >1 independent signal. Fine-mapping at OBFC1 indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). We further identified two novel genes, DCLRE1B (SNM1B) and PARN, using a multi-variant gene-based approach.

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