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Meta-Analysis
. 2019 Jun 6;10(1):2491.
doi: 10.1038/s41467-019-10443-2.

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

Rajkumar Dorajoo  1 , Xuling Chang  2   3 , Resham Lal Gurung  4 , Zheng Li  1 , Ling Wang  1 , Renwei Wang  5 , Kenneth B Beckman  6 , Jennifer Adams-Haduch  5 , Yiamunaa M  4 , Sylvia Liu  4 , Wee Yang Meah  1 , Kar Seng Sim  1 , Su Chi Lim  4   7   8 , Yechiel Friedlander  9 , Jianjun Liu  1   10 , Rob M van Dam  8   10 , Jian-Min Yuan  5   11 , Woon-Puay Koh  8   12 , Chiea Chuen Khor  13   14 , Chew-Kiat Heng  15   16
Affiliations
Meta-Analysis

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

Rajkumar Dorajoo et al. Nat Commun. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
LTL associations in the SCHS discovery GWAS. a Seven hits at chromosome 1, 3, 4, 5, 8, 10, and 14 were identified beyond the genome-wide significance threshold (score test P < 5 × 10−8, red line) and 4 hits at chromosome 7, 11, 20, and 22 were identified beyond the suggestive significance threshold (score test P < 1 × 10−6, blue line). b QQ-plot of observed compared to expected P-values in the SCHS discovery GWAS indicated minimal inflation of study results (λ = 1.043)
Fig. 2
Fig. 2
Regional SNP associations at the OBFC1 gene locus in the SCHS discovery GWAS. a Association of lead SNP identified in the SCHS (rs12415148). b Association of previously identified index SNP from European GWAS studies (rs9420907). Lead SNP indicated as purple diamonds. LD (r2) data of SNPs based on ASN panels of 1000Genome database. Plots plotted using LocusZoom (http://csg.sph.umich.edu/locuszoom/)
Fig. 3
Fig. 3
Regional SNP associations at the RTEL1 gene locus in the SCHS discovery GWAS. a Association of lead SNP identified in the SCHS (rs41309367). b Association of previously identified index SNP from European GWAS studies (rs755017). c Association of previously identified index SNP from South Asian GWAS studies (rs2297439). Lead SNP indicated as purple diamonds. LD (r2) data of SNPs based on ASN panels of 1000Genome database. Plots plotted using LocusZoom (http://csg.sph.umich.edu/locuszoom/)
Fig. 4
Fig. 4
Regional SNP associations at the DCAF4 gene locus in the trans-ethnic meta-analysis. a Association of lead SNP identified in the study (rs2302588). b Association of previously identified index SNP from European GWAS studies (rs2535913). Lead SNP indicated as purple diamonds. LD (r2) data of SNPs based on ASN panels of 1000Genome database. Plots plotted using LocusZoom (http://csg.sph.umich.edu/locuszoom/)
Fig. 5
Fig. 5
Gene set enrichment of mapped regional genes for LTL association in previous GWAS studies. Enrichment P-values adjusted for Bonferroni corrections and proportion indicates the percentage of input LTL associated genes that overlap with genes implicated in previous GWAS traits and diseases
See this image and copyright information in PMC

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