Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans

Abstract

Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.

Figure 1.

Manhattan plot of discovery meta-analysis.

Figure 2.

Regional plots of chromosome 17 (A) and 19 (B) loci. SNPs are plotted by position on chromosome against association (−log10 P-value) with LTL using discovery GWAS meta-analysis data. In each panel, the SNP with the strongest association is denoted with a purple dot: the P-value attached represents the final P-value obtained in the meta-analysis (Table 2). Estimated recombination rates (from HapMap-CEU) are plotted in blue to reflect the local LD structure on a secondary Y-axis. The SNPs surrounding the most significant SNP (purple dot) are color-coded (see legend) to reflect their LD with the lead SNP (using pair-wise r²-values from HapMap CEU). Genes position, as well as transcription direction, is shown below the plots (using data from the UCSC genome browser, genome.ucsc.edu).