title: Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  We 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).
  
  
  CONCLUSIONS
  Sequencing analysis of family-based associations for age-related phenotypes can identify rare or novel variants.
authors.affiliation: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St. Louis, MO, 63108, USA.|Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St. Louis, MO, 63108, USA.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Druley
authors.affiliation: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St. Louis, MO, 63108, USA.|Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St. Louis, MO, 63108, USA.|Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Shiow J
authors.initials: SJ
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St. Louis, MO, 63108, USA.|Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Qunyuan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St. Louis, MO, 63108, USA.|Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: E Warwick
authors.initials: EW
authors.lastname: Daw
authors.affiliation: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St. Louis, MO, 63108, USA.|Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Haley J
authors.initials: HJ
authors.lastname: Abel
authors.affiliation: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St. Louis, MO, 63108, USA.|Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St. Louis, MO, 63108, USA.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Chasnoff
authors.affiliation: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St. Louis, MO, 63108, USA.|Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St. Louis, MO, 63108, USA.
authors.forename: Enrique I
authors.initials: EI
authors.lastname: Ramos
authors.affiliation: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St. Louis, MO, 63108, USA.|Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St. Louis, MO, 63108, USA.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Levinson
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Bharat
authors.initials: B
authors.lastname: Thyagarajan
authors.affiliation: Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Newman
authors.affiliation: The Danish Aging Research Center, Epidemiology, University of Southern Denmark, Odense, Denmark.
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.affiliation: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St. Louis, MO, 63108, USA. mprovince@wustl.edu.|Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. mprovince@wustl.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Province
mesh_terms: D000368:Aged; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D010375:Pedigree; D010641:Phenotype
keywords: Aging; Family; Genetics; Genomics; Geriatrics; Pedigrees; Sequencing