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

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 in ACD and RTEL1 . 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 large SRSF2 -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. ### Competing Interest Statement OB,RD,SV,SW,AN,JM,FH,KS,NR,HO,AP,DV,QW,RM,SW,KC,MF,QW,MP and SP are current employees and/or stockholders of AstraZeneca ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank data use (Project Application Numbers 68601 and 26041) was approved by the UK Biobank according to their established access procedures. UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB), and as such researchers using UK Biobank data do not require separate ethical clearance and can operate under the RTB approval. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors