Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Abstract

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7 , MOB1B , CARMIL1 , PRRC2A , TERF2, and RFWD3 , and our results support recently identified PARP1, POT1 , ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

Genetically predicted telomere length is associated with clonal somatic copy number alterations in peripheral leukocytes

“…Furthermore, the original TOPMed GWAS results did not include standard errors for the weights of the 22 telomere length-associated variants [23], which precluded rigorous MR tests to be conducted with our original panel of included variants. Instead, MR tests were conducted using available summary statistics from a telomere length GWAS performed in Europeans [34]. This alternative telomere length variant panel has considerable overlap with our original panel, but also includes a few novel loci.…”

Are long telomeres better than short? Relative contributions of genetically predicted telomere length to neoplastic and non-neoplastic disease risk and population health burden

“…Repeating our analysis on another recently published Mendelian Randomization study using 52 SNPs associated with LTL and health data from the UK Biobank reveals a similar pattern of contribution to the incidence and burden of neoplastic disease [38]. The Li et al study identified five cancer types (thyroid cancer, lymphoma and multiple myeloma, leukemia, lung cancer, skin cancer (including melanoma)) and two benign conditions of abnormal cellular proliferation (uterine fibroid, benign prostatic hyperplasia (BPH)) that were significantly associated with long gTL.…”

“…Odds ratios (ORs) of disease associated with gTL telomere length were taken from the 2017 Haycock et al meta-analysis, which identified 16 SNPs as a genetic proxy for telomere length in order to assess the relationship with 56 primary-outcome diseases in a Mendelian Randomization design [49]. An additional 7 ORs of disease were taken from an original publication by Li et al [38], in which ORs of disease were calculated for 122 diseases using 52 independent variants. Only odds ratios with statistical significance were included in the present analysis.…”

Association between genetically predicted telomere length and facial skin aging in the UK Biobank: a Mendelian randomization study

“…The European Network for Genetic and Genomic Epidemiology (ENGAGE) conducted a genome-wide association study (GWAS) for leukocyte TL in 78,592 individuals of European ancestry [10]. Mean leukocyte TL was measured in a mixed population of leukocytes, and measurements were conducted using an established quantitative polymerase chain reaction technique which expressed TL as a ratio of the telomere repeat number (T) to a single-copy gene (S) [11].…”