Genome wide association and linkage analyses identified three loci—4q25, 17q23.2, and 10q11.21—associated with variation in leukocyte telomere length: the Long Life Family Study

Joseph H Lee,Candace M Kammerer,Kaare Christensen,Mary Feitosa,Rong Cheng,Michael Province,Jason L Sanders,Nicole Schupf,Thomas Perls,Lawrence S Honig,Richard Mayeux,Todd Druley,Harold Bae,Shiow J Lin,Min S Kang

doi:10.3389/fgene.2013.00310

Abstract

Leukocyte telomere length is believed to measure cellular aging in humans, and short leukocyte telomere length is associated with increased risks of late onset diseases, including cardiovascular disease, dementia, etc. Many studies have shown that leukocyte telomere length is a heritable trait, and several candidate genes have been identified, including TERT, TERC, OBFC1, and CTC1. Unlike most studies that have focused on genetic causes of chronic diseases such as heart disease and diabetes in relation to leukocyte telomere length, the present study examined the genome to identify variants that may contribute to variation in leukocyte telomere length among families with exceptional longevity. From the genome wide association analysis in 4,289 LLFS participants, we identified a novel intergenic SNP rs7680468 located near PAPSS1 and DKK2 on 4q25 (p = 4.7E-8). From our linkage analysis, we identified two additional novel loci with HLOD scores exceeding three, including 4.77 for 17q23.2, and 4.36 for 10q11.21. These two loci harbor a number of novel candidate genes with SNPs, and our gene-wise association analysis identified multiple genes, including DCAF7, POLG2, CEP95, and SMURF2 at 17q23.2; and RASGEF1A, HNRNPF, ANF487, CSTF2T, and PRKG1 at 10q11.21. Among these genes, multiple SNPs were associated with leukocyte telomere length, but the strongest association was observed with one contiguous haplotype in CEP95 and SMURF2. We also show that three previously reported genes—TERC, MYNN, and OBFC1—were significantly associated with leukocyte telomere length at pempirical < 0.05.

Highlights

Telomere shortening is a marker of in vivo cellular aging, and leukocyte telomere length is related to life span (Holt et al, 1996; Chadwick and Cardew, 1997; Shay and Wright, 2001; Aviv et al, 2006; Christensen et al, 2006; Armanios and Blackburn, 2012)
Individuals with short leukocyte telomere length are at an increased risk of age-related diseases and premature subsequent death compared with aged individuals with longer telomeres (Jeanclos et al, 1998; Epel et al, 2004; Aviv, 2009, 2012; Kaplan et al, 2009; Honig et al, 2012; Shaffer et al, 2012; Ye et al, 2013)
To identify genetic variants contributing to variation in leukocyte telomere length, we analyzed data from a large cohort of families that had multiple family members who survived to exceptionally old age

Summary

INTRODUCTION

Telomere shortening is a marker of in vivo cellular aging, and leukocyte telomere length is related to life span (Holt et al, 1996; Chadwick and Cardew, 1997; Shay and Wright, 2001; Aviv et al, 2006; Christensen et al, 2006; Armanios and Blackburn, 2012). A meta-analysis (Mangino et al, 2012) identified CTC1 (conserved telomere maintenance component 1, 17p13.1) and ZNF676 (zinc finger protein 676, 19p12) as candidate genes for telomere homeostasis in humans, and confirmed that minor variants of OBFC1 on 10q24.33 was associated with shorter leukocyte telomere length. Their function is not certain, these genes appear to be involved in maintenance of chromosome structures. To identify genetic variants contributing to variation in leukocyte telomere length, we analyzed data from a large cohort of families that had multiple family members who survived to exceptionally old age (the Long Life Family Study). A heterogeneity model for linkage analysis was applied to account for possible genetic heterogeneity across families since different families may achieve longevity through different means

MATERIALS AND METHODS

RESULTS

DISCUSSION

A2 Measured genotype multipoint LOD*