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

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.

Citation

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, 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, NHLBI CARE Network, Angel Cy Mak, Ruth Jf Loos, Rajesh Kumar, Charles Kooperberg, Barbara A Konkle, Shannon Kelly, Sharon Lr 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, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group, 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. Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed. Cell genomics. 2022 Jan 12;2(1)

PMID: 35530816

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