Genetic regulation of newborn telomere length is mediated and modified by DNA methylation

Telomere length at birth determines later life telomere length and potentially predicts ageing-related diseases. However, the genetic and epigenetic settings of telomere length in newborns have not been analyzed. In addition, no study yet has reported how the interplay between genetic variants and genome-wide cytosine methylation explains the variation in early-life telomere length. In this study based on 281 mother-newborn pairs from the ENVIRONAGE birth cohort, telomere length and whole-genome DNA methylation were assessed in cord blood and 26 candidate single nucleotide polymorphism related to ageing or telomere length were genotyped. We identified three genetic variants associated with cord blood telomere length and 57 cis methylation quantitative trait loci (cis-mQTLs) of which 22 mQTLs confirmed previous findings and 35 were newly identified. Five SNPs were found to have significant indirect effects on cord blood telomere length via the mediating CpGs. The association between rs911874 (SOD2) and newborn telomere length was modified by nearby DNA methylation indicated by a significant statistical interaction. Our results suggest that DNA methylation in cis might have a mediation or modification effect on the genetic difference in newborn telomere length. This novel approach warrants future follow-up studies that are needed to further confirm and extend these findings.The ENVIRONAGE birth cohort is supported by grants from the European Research Council (Grant No. ERC-2012-StG310898), the Flemish Scientific Fund (FWO, Grant No. G073315N) and Kom Op Tegen Kanker (KOTK). DSM (FWO grant 12X9620N) is postdoctoral fellows of the Flanders Research Foundation. JH was partly funded by a postdoctoral research fellow grant from the Research Foundation–Flanders (FWO) (no. 12J9516N). This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 874583 (ATHLETE)