Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study

BMC Geriatrics

Research Article

Todd E. Druley¹  Sara E. Chasnoff¹  Enrique I. Ramos¹  Benjamin T. Levinson¹  Shiow J. Lin²  Haley J. Abel²  Michael A. Province²  Qunyuan Zhang²  Lihua Wang²  E. Warwick Daw²  Anne B. Newman³  Bharat Thyagarajan⁴  Richard Mayeux⁵  Joseph H. Lee⁶  Kaare Christensen⁷ 

[1] Center for Genome Sciences and Systems Biology, Washington University School of Medicine, Campus Box 8116, 660 South Euclid Avenue, 63108, St. Louis, MO, USA;Department of Pediatrics, Washington University School of Medicine, Campus Box 8116, 660 South Euclid Avenue, 63108, St. Louis, MO, USA;Center for Genome Sciences and Systems Biology, Washington University School of Medicine, Campus Box 8116, 660 South Euclid Avenue, 63108, St. Louis, MO, USA;Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA;Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA;Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA;Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York City, NY, USA;Sergievsky Center, College of Physicians and Surgeons, Columbia University New York, New York, NY, USA;Taub Institute, College of Physicians and Surgeons, Columbia University New York, New York, NY, USA;Department of Epidemiology, School of Public Health, Columbia University New York, New York, NY, USA;The Danish Aging Research Center, Epidemiology, University of Southern Denmark, Odense, Denmark;

关键词: Genomics;    Aging;    Genetics;    Geriatrics;    Pedigrees;    Family;    Sequencing;   

DOI  :  10.1186/s12877-016-0253-y

 received in 2015-05-07, accepted in 2016-04-04,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundThe Long Life Family Study (LLFS) is an international study to identify the genetic components of various healthy aging phenotypes. We hypothesized that pedigree-specific rare variants at longevity-associated genes could have a similar functional impact on healthy phenotypes.MethodsWe performed custom hybridization capture sequencing to identify the functional variants in 464 candidate genes for longevity or the major diseases of aging in 615 pedigrees (4,953 individuals) from the LLFS, using a multiplexed, custom hybridization capture. Variants were analyzed individually or as a group across an entire gene for association to aging phenotypes using family based tests.ResultsWe found significant associations to three genes and nine single variants. Most notably, we found a novel variant significantly associated with exceptional survival in the 3’ UTR OBFC1 in 13 individuals from six pedigrees. OBFC1 (chromosome 10) is involved in telomere maintenance, and falls within a linkage peak recently reported from an analysis of telomere length in LLFS families. Two different algorithms for single gene associations identified three genes with an enrichment of variation that was significantly associated with three phenotypes (GSK3B with the Healthy Aging Index, NOTCH1 with diastolic blood pressure and TP53 with serum HDL).ConclusionsSequencing analysis of family-based associations for age-related phenotypes can identify rare or novel variants.

【 授权许可】

CC BY   
© Druley et al. 2016