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) 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 indicated the independent signals colocalized with cell-type specific eQTLs for (). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, () and . In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes.

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References

Conomos M, Miller M, Thornton T . Robust inference of population structure for ancestry prediction and correction of stratification in the presence of relatedness. Genet Epidemiol. 2015; 39(4):276-93. PMC: 4836868. DOI: 10.1002/gepi.21896. View

Zhou B, Shi J, Whittemore A . Optimal methods for meta-analysis of genome-wide association studies. Genet Epidemiol. 2011; 35(7):581-91. PMC: 3197760. DOI: 10.1002/gepi.20603. View

Almasy L, Blangero J . Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet. 1998; 62(5):1198-211. PMC: 1377101. DOI: 10.1086/301844. View

Giambartolomei C, Vukcevic D, Schadt E, Franke L, Hingorani A, Wallace C . Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 2014; 10(5):e1004383. PMC: 4022491. DOI: 10.1371/journal.pgen.1004383. View

Mangino M, Hwang S, Spector T, Hunt S, Kimura M, Fitzpatrick A . Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans. Hum Mol Genet. 2012; 21(24):5385-94. PMC: 3510758. DOI: 10.1093/hmg/dds382. View

Saxena R, Bjonnes A, Prescott J, Dib P, Natt P, Lane J . Genome-wide association study identifies variants in casein kinase II (CSNK2A2) to be associated with leukocyte telomere length in a Punjabi Sikh diabetic cohort. Circ Cardiovasc Genet. 2014; 7(3):287-95. PMC: 4106467. DOI: 10.1161/CIRCGENETICS.113.000412. View

Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A . Integrative analysis of 111 reference human epigenomes. Nature. 2015; 518(7539):317-30. PMC: 4530010. DOI: 10.1038/nature14248. View

Oglesbee M, Herdman A, Passmore G, Hoffman W . Diabetic ketoacidosis increases extracellular levels of the major inducible 70-kDa heat shock protein. Clin Biochem. 2005; 38(10):900-4. DOI: 10.1016/j.clinbiochem.2005.05.011. View

Li C, Stoma S, Lotta L, Warner S, Albrecht E, Allione A . Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length. Am J Hum Genet. 2020; 106(3):389-404. PMC: 7058826. DOI: 10.1016/j.ajhg.2020.02.006. View

10.

Jagadeesh K, Wenger A, Berger M, Guturu H, Stenson P, Cooper D . M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity. Nat Genet. 2016; 48(12):1581-1586. DOI: 10.1038/ng.3703. View

11.

Ahn D, Ozer H, Hancioglu B, Lesinski G, Timmers C, Bekaii-Saab T . Whole-exome tumor sequencing study in biliary cancer patients with a response to MEK inhibitors. Oncotarget. 2015; 7(5):5306-12. PMC: 4868687. DOI: 10.18632/oncotarget.6632. View

12.

Chen H, Huffman J, Brody J, Wang C, Lee S, Li Z . Efficient Variant Set Mixed Model Association Tests for Continuous and Binary Traits in Large-Scale Whole-Genome Sequencing Studies. Am J Hum Genet. 2019; 104(2):260-274. PMC: 6372261. DOI: 10.1016/j.ajhg.2018.12.012. View

13.

McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood A, Teumer A . A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016; 48(10):1279-83. PMC: 5388176. DOI: 10.1038/ng.3643. View

14.

Codd V, Mangino M, van der Harst P, Braund P, Kaiser M, Beveridge A . Common variants near TERC are associated with mean telomere length. Nat Genet. 2010; 42(3):197-9. PMC: 3773906. DOI: 10.1038/ng.532. View

15.

Zhang M, Wang R, Wang Y, Diao F, Lu F, Gao D . The CXXC finger 5 protein is required for DNA damage-induced p53 activation. Sci China C Life Sci. 2009; 52(6):528-38. DOI: 10.1007/s11427-009-0083-7. View

16.

Wu M, Reuter M, Lilie H, Liu Y, Wahle E, Song H . Structural insight into poly(A) binding and catalytic mechanism of human PARN. EMBO J. 2005; 24(23):4082-93. PMC: 1356309. DOI: 10.1038/sj.emboj.7600869. View

17.

Levy D, Neuhausen S, Hunt S, Kimura M, Hwang S, Chen W . Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. Proc Natl Acad Sci U S A. 2010; 107(20):9293-8. PMC: 2889047. DOI: 10.1073/pnas.0911494107. View

18.

Kimura M, Stone R, Hunt S, Skurnick J, Lu X, Cao X . Measurement of telomere length by the Southern blot analysis of terminal restriction fragment lengths. Nat Protoc. 2010; 5(9):1596-607. DOI: 10.1038/nprot.2010.124. View

19.

Liu Y, Cao L, Li Z, Zhou D, Liu W, Shen Q . A genome-wide association study identifies a locus on TERT for mean telomere length in Han Chinese. PLoS One. 2014; 9(1):e85043. PMC: 3897378. DOI: 10.1371/journal.pone.0085043. View

20.

Nersisyan L, Arakelyan A . Computel: computation of mean telomere length from whole-genome next-generation sequencing data. PLoS One. 2015; 10(4):e0125201. PMC: 4414351. DOI: 10.1371/journal.pone.0125201. View