Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies

Rajkumar Dorajoo,Jennifer Adams-Haduch,Renwei Wang,Ling Wang,Wee Yang Meah,Xuling Chang,Resham L Gurung ,Yiamunaa M,Woon‐Puay Koh ,Jian‐Min Yuan ,Jing Liu ,Sylvia Liu,Chiea Chuen Khor,Zheng Li,Kenneth B Beckman,Yechiel Friedlander,Kar Seng Sim,Su Chi Lim,Rob M Van Dam ,Chew‐Kiat Heng

doi:10.1038/s41467-019-10443-2

Abstract

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P < 5 × 10−8). Several of these contain candidate genes (TINF2, PARP1, TERF1, ATM and POT1) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6, NKX2-3 and TYMS. We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804–0.906), P = 1.88 × 10−7] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections (P = 7.44 × 10−4) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence.

Highlights

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility
We further show that shorter LTL protects especially strongly against respiratory disease deaths in the Singapore Chinese population
At 3 other loci, we identified lead SNP associations in the Singapore Chinese Health Study (SCHS) discovery Genome-wide association studies (GWAS) that were in LD (r2 > 0.6) with previously identified index SNPs from European GWAS studies[16,17,18,19,20,21]

Summary

Introduction

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. The telomerase enzyme, which elongates telomeres and promotes cell survival and proliferation, is activated in most human cancers and longer LTL confers increased risks for several types of cancers[11,12]. These reports suggest a complex relationship between cellular telomere length, biological aging, and risks of various chronic diseases. Genome-wide association studies (GWAS) indicate that LTL is a complex polygenic trait These genetic studies have identified at least eight different gene loci associated with LTL16–22. We further show that shorter LTL protects especially strongly against respiratory disease deaths in the Singapore Chinese population

Methods

Results

Conclusion