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BMC Geriatrics
Published in: BMC Geriatrics 1/2016

Open Access 01-12-2016 | Research article

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

Authors: Todd E. Druley, Lihua Wang, Shiow J. Lin, Joseph H. Lee, Qunyuan Zhang, E. Warwick Daw, Haley J. Abel, Sara E. Chasnoff, Enrique I. Ramos, Benjamin T. Levinson, Bharat Thyagarajan, Anne B. Newman, Kaare Christensen, Richard Mayeux, Michael A. Province

Published in: BMC Geriatrics | Issue 1/2016

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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.
Appendix
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Metadata
Title
Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study
Authors
Todd E. Druley
Lihua Wang
Shiow J. Lin
Joseph H. Lee
Qunyuan Zhang
E. Warwick Daw
Haley J. Abel
Sara E. Chasnoff
Enrique I. Ramos
Benjamin T. Levinson
Bharat Thyagarajan
Anne B. Newman
Kaare Christensen
Richard Mayeux
Michael A. Province
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Geriatrics / Issue 1/2016
Electronic ISSN: 1471-2318
DOI
https://doi.org/10.1186/s12877-016-0253-y

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