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

doi:10.3389/fgene.2013.00310

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

Front Genet. 2014 Jan 17:4:310. doi: 10.3389/fgene.2013.00310. eCollection 2013.

Authors

Joseph H Lee¹, Rong Cheng², Lawrence S Honig³, Mary Feitosa⁴, Candace M Kammerer⁵, Min S Kang⁶, Nicole Schupf⁷, Shiow J Lin⁴, Jason L Sanders⁸, Harold Bae⁹, Todd Druley¹⁰, Thomas Perls¹¹, Kaare Christensen¹², Michael Province⁴, Richard Mayeux¹³

Affiliations

¹ Sergievsky Center, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Taub Institute, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Department of Epidemiology, School of Public Health, Columbia University New York, NY, USA.
² Sergievsky Center, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Taub Institute, College of Physicians and Surgeons, Columbia University New York, NY, USA.
³ Sergievsky Center, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Taub Institute, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Department of Neurology, College of Physicians and Surgeons, Columbia University New York, NY, USA.
⁴ Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine St. Louis, MO, USA.
⁵ Department of Epidemiology, University of Pittsburgh Pittsburgh, PA, USA ; Department of Human Genetics, University of Pittsburgh Pittsburgh, PA, USA ; Center for Aging and Population Health, University of Pittsburgh Pittsburgh, PA, USA.
⁶ Taub Institute, College of Physicians and Surgeons, Columbia University New York, NY, USA.
⁷ Sergievsky Center, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Taub Institute, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Department of Epidemiology, School of Public Health, Columbia University New York, NY, USA ; Department of Psychiatry, College of Physicians and Surgeons, Columbia University New York, NY, USA.
⁸ Department of Epidemiology, University of Pittsburgh Pittsburgh, PA, USA ; Center for Aging and Population Health, University of Pittsburgh Pittsburgh, PA, USA.
⁹ Department of Biostatistics, Boston University Medical Center Boston, MA, USA.
¹⁰ Department of Pediatrics and Genetics, Washington University School of Medicine St. Louis, MO, USA.
¹¹ Department of Medicine, Boston University Medical Center Boston, MA, USA.
¹² The Danish Aging Research Center, Epidemiology, University of Southern Denmark Odense, Denmark.
¹³ Sergievsky Center, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Taub Institute, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Department of Epidemiology, School of Public Health, Columbia University New York, NY, USA ; Department of Neurology, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Department of Psychiatry, College of Physicians and Surgeons, Columbia University New York, NY, USA.

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 p empirical < 0.05.

Keywords: aging; familial longevity; family-based study; genome wide association and linkage; novel genes; telomere length.

Abstract

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