Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed
Creators: name: Blackwell, T.W.
name: Chen, Z.
name: White, M.J.
name: Cox, N.J.
name: Darbar, D.
name: Smith, A.V.
name: Deka, R.
name: Daya, M.
name: Sheu, W.H.-H.
name: Wheeler, M.M.
name: Rotter, J.I.
name: Arvanitis, M.
name: Barwick, L.
name: Minster, R.L.
name: Gladwin, M.T.
name: Peralta, J.M.
name: Fingerlin, T.E.
name: Cupples, L.A.
name: Iyer, K.R.
name: Mathias, R.A.
name: Williams, L.K.
name: Aviv, A.
name: Liu, C.
name: Hidalgo, B.A.
name: O'Connell, J.
name: DeMeo, D.L.
name: Sinner, M.F.
name: Levin, A.M.
name: Nouraie, M.
name: Loos, R.J.F.
name: Psaty, B.M.
name: de Andrade, M.
name: Naseri, T.
name: NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
name: Heavner, B.
name: Mak, A.C.Y.
name: McGarvey, S.T.
name: Roden, D.
name: Chen, Y.-D.I.
name: Jain, D.
name: Palmer, N.D.
name: Keener, R.
name: Conomos, M.P.
name: Kardia, S.L.R.
name: Johnson, W.C.
name: Moscati, A.
name: Launer, L.
name: Seidman, C.
name: Taylor, J.G., VI
name: Lee, J.
name: Peyser, P.A.
name: TOPMed Hematology and Hemostasis Working Group
name: Rafaels, N.
name: Nekhai, S.
name: Laurie, C.A.
name: Johnsen, J.M.
name: Sciurba, F.
name: Garrett, M.E.
name: Taylor, K.D.
name: Custer, B.
name: Smith, N.L.
name: Raby, B.A.
name: Blangero, J.
name: Lane, J.
name: Hwang, S.-J.
name: Hou, L.
name: Weinstock, J.S.
name: Cade, B.E.
name: Telen, M.J.
name: Bowden, D.W.
name: Montgomery, C.G.
name: Weiss, S.T.
name: Ruczinski, I.
name: Levy, D.
name: Keramati, A.
name: TOPMed Structural Variation Working Group
name: Curran, J.E.
name: Wen, F.
name: Thornton, T.
name: Kenny, E.E., The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States, Center for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States
name: Schwartz, D.A.
name: Cho, M.H.
name: Brody, J.A.
name: Perry, J.A.
name: Lasky-Su, J.
name: Eng, C.
name: Zhao, W.
name: Pankratz, N.
name: de las Fuentes, L.
name: Irvin, M.R.
name: Kumar, R.
name: Heckbert, S.R.
name: Bleecker, E.R.
name: Boerwinkle, E.
name: Becker, L.C.
name: Gui, H.
name: Ashley-Koch, A.E.
name: He, J.
name: Mitchell, B.D.
name: Kelly, S.
name: Fornage, M.
name: Smith, J.A.
name: Gogarten, S.M.
name: Gelb, B.D.
name: Ellinor, P.T.
name: Yanek, L.R.
name: Liu, S.
name: McHugh, C.P.
name: Armanios, M.
name: Kooperberg, C.
name: Reiner, A.P.
name: Sabino, E.C.
name: Yang, I.V.
name: Raffield, L.M.
name: Aslibekyan, S.
name: Reupena, M.S.
name: Shoemaker, M.B.
name: Abecasis, G.
name: Laurie, C.C.
name: Gilliland, F.D.
name: Miller-Fleming, T.W.
name: Guo, X.
name: Meyers, D.A.
name: Burchard, E.G.
name: Battle, A.
name: Bis, J.C.
name: Correa, A.
name: Arnett, D.K.
name: Kaab, S.
name: Kaplan, R.
name: North, K.E.
name: Auer, P.L.
name: Islam, T.
name: Vasan, R.S.
name: Taub, M.A.
name: Chang, Y.P.C.
name: Nickerson, D.A.
name: Silverman, E.K.
name: Tracy, R.P.
name: Celedón, J.C.
name: Freedman, B.I.
name: Tiwari, H.K.
name: Redline, S.
name: Albert, C.
name: Wiggins, K.L.
name: Zhang, Y.
name: Weeks, D.E.
name: Konkle, B.A.
name: Rich, S.S.
name: Wilson, J.G.
name: Barnes, K.C.
Publisher: name: Cell Press
Year: 2022

description: 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 &lt; 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.