Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population

Abstract

The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10^-14-6.94×10^-10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR_95%CI = 1.544 (1.173, 2.032), P_Adj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR_95%CI = 1.123 (1.051, 1.201), P_adj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers.

Fig. 1. Low-frequency LTL associations in the SCHS Discovery dataset (N = 20,177).

a Three loci at chromosome 7, 8, and 10 were identified beyond the genome-wide significance threshold (score test P < 3.117 × 10⁻⁸, red line). b QQ-plot of observed compared to expected P-values indicated minimal inflation of study results (λ = 1.0098).

Fig. 2. Mediation analysis to quantify how much the genetic variant affects incident cancer through LTL.

a Proportion of rs79617270 total effects on colon cancer mediated through LTL = 4.76. b Proportion of wGRS total effects on lung adenocarcinoma mediated through LTL = 24.92%.