Telomeres protect the ends of linear chromosomes and telomere length (TL) decreases as humans age. Individuals with extremely short telomeres present with Short Telomere Syndromes (STS). To gain insight into the genetic regulation of TL, prior work from our group and others leveraged genome-wide association studies to examine the role of common genetic variation in TL genetics. This strategy successfully identified novel genes involved in TL regulation, some of which we experimentally validated in cell culture. However, this approach ignores the effects of rare genetic variation, which can have larger effect sizes and impact genes under strong constraint.

Studies of rare variant effects on TL have improved our understanding of TL biology, but have largely required laborious STS patient single pedigree studies. We sought to leverage TL estimates and rare variant data from the Trans-Omics for Precision Medicine (TOPMed) Program to broadly examine the impact of rare variation on TL. Previously we developed Watershed, a Bayesian hierarchical model, which uses paired mutli-omic data (whole genome sequencing, expression, splicing, methylation, and/or protein levels) to prioritize rare variants causing significant disruption of at least one of the molecular signals. We used multi-omic data and TL estimates from the MESA cohort to train the Watershed model and observed that, in individuals with extreme TL, it prioritized a rare variant affecting expression of TPP1, a known TL regulation gene. We will expand our analysis across TOPMed and incorporate multi-omic data where available. Examination of highly weighted variants in individuals with extreme TL (extremely long or extremely short) relative to average TL will potentially identify novel genes involved in TL regulation. TOPMed has TL estimates on people with an age range of 0-98 years old; we will leverage the scale of TOPMed to examine the interplay between TL genetic regulation and multi-omic signals over age. Further, we will apply our model to multi-omic data from STS patients to improve their genetic diagnosis. Together this work has utility in improving diagnosis of individuals with disease caused by extreme TL and furthering our understanding of the molecular mechanisms governing TL regulation.