Prior GWAS have identified 11 loci harboring common genetic determinants of telomere length (TL); several of these loci have been implicated in human disease. These studies have relied on genotype array/imputation data and TL generated through qPCR or Southern Blot. Large-scale whole genome sequencing (WGS) gives the opportunity to analyze TL data on large numbers of subjects with extensive phenotyping to (1) generate estimates of TL; (2) expand our knowledge of genetic determinants of TL; and (3) add to our understanding of the role these variants may play in disease etiology.

WGS data were generated within the NHLBI Trans-Omics for Precision Medicine (TOPMed) project, and TL was estimated on 93,219 samples using TelSeq software. We performed single variant association tests using mega-analysis, combining data from 27 TOPMed studies on a subset of 49,899 subjects within the current genotype data freeze in TOPMed (~86 million variants after filtering sites with minor allele count below 5). We used a two-stage approach, initially screening variants with a standard linear model adjusting for sex and study, followed by a linear mixed-model also adjusting for population structure and relatedness on the subset of variants with p<0.01 from the first-stage analysis (conducted on the Analysis Commons, http://analysiscommons.com/).

We discovered four novel TL loci with common variants (MAF>1%), including three with strong biological interest: (1) TERF1 (p=4.8x10-9), encoding a telomeric repeat-binding factor; (2) RFWD3 (p=2.7x10-9), encoding a protein involved in DNA damage repair; and (3) TINF2 (p=3.5x10-10), a component of the shelterin complex, which protects against telomere shortening; and (4) LINC01429 (p=3.0x10-8). There were 47 rare variants that achieved genome-wide significance for TL. We replicated 6 common loci previously associated with TL: NAF1 (p= 4.2x10-11), OBFC1 (p=6.4x10-16), TERC (p=4.9x10-20), TERT (p=1.3x10-26), ZNF208/ZNF676 (p=1.5x10-8), and RTEL1 (p=7.8x10-11).

Our TOPMed Working Group is examining methods to correct for batch effects in these TL data. In the near future, we will include an additional ~45,000 TOPMed subjects with WGS that will improve our ability to (1) fine-map the common variant loci; (2) identify novel loci through gene-based approaches; and (3) given known differences in TL by population, maximize our power to identify genetic determinants within groups.