Genetic architecture of telomere length in 462,675 UK Biobank whole-genome sequences

Abstract

Telomeres protect the ends of chromosomes from damage, and genetic regulation of their length is associated with human disease and ageing. We developed a joint telomere length (TL) metric, combining both qPCR and whole genome sequencing (WGS) measurements across 462,675 UK Biobank participants that increased our ability to capture TL heritability by 36% (h2mean=0.058 to h2combined=0.079) and improved predictions of age. Exome-wide rare variant (minor allele frequency<0.001) and gene-level collapsing association studies identified 53 variants and 22 genes significantly associated with TL that included allelic series inACDandRTEL1. Five of the 31 rare-variant TL associated genes (16%) were also known drivers of clonal haematopoiesis (CH), prompting somatic variant analyses. Stratifying by CH clone size, we uncovered novel gene-specific associations with TL, including lengthened telomeres in individuals with largeSRSF2-mutant clones, in contrast to the progressive telomere shortening observed with increasing clonal expansions driven by other CH genes. Our findings demonstrate the impact of rare variants on TL with larger effects in genes associated with CH, a precursor of myeloid cancers and several other non-malignant human diseases. Telomere biology is likely to be an important focus for the prevention and treatment of these conditions.

Characterising the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases

“…In combination with the confirmed association between genetically predicted longer telomere length and increased prostate cancer risk 38 , this implicates telomere maintenance as a potential mechanism for SAMHD1 -mediated predisposition to prostate cancer. Conversely, rare deleterious variants in TERT are associated with shorter telomeres 44 , consistent with the finding here that a missense TERT variant is associated with a decreased risk of developing prostate cancer.…”

“…It acts as a dNTPase, participates in innate immune regulation, maintains genome integrity and is recurrently somatically mutated across multiple tumour types 42,43 . It is notable that the same QV model strongly associated with prostate cancer risk was previously found to be associated with longer telomere length 44 . In combination with the confirmed association between genetically predicted longer telomere length and increased prostate cancer risk 38 , this implicates telomere maintenance as a potential mechanism for SAMHD1 -mediated predisposition to prostate cancer.…”

Comparative analysis of 136,401 Admixed Americans and 419,228 Europeans reveals ancestry-specific genetic determinants of clonal haematopoiesis

“…Emerging evidence from European populations suggests that CH risk is influenced by telomere length 15,24–26 . Therefore, we performed telomere length GWAS among 9,649 MCPS individuals with WGS-derived telomere length inferred from TelSeq 27 (Extended Data Fig.…”