Dataset Information

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

ABSTRACT: 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.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.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).Sequencing analysis of family-based associations for age-related phenotypes can identify rare or novel variants.

SUBMITTER: Druley TE

PROVIDER: S-EPMC4826550 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Druley Todd E TE Wang Lihua L Lin Shiow J SJ Lee Joseph H JH Zhang Qunyuan Q Daw E Warwick EW Abel Haley J HJ Chasnoff Sara E SE Ramos Enrique I EI Levinson Benjamin T BT Thyagarajan Bharat B Newman Anne B AB Christensen Kaare K Mayeux Richard R Province Michael A MA

BMC geriatrics 20160409

<h4>Background</h4>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.<h4>Methods</h4>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 individu ...[more]

PMID: 27060904

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Project description:BackgroundWith the advent of next-generation sequencing (NGS) technologies, researchers are now generating a deluge of data on high dimensional genomic variations, whose analysis is likely to reveal rare variants involved in the complex etiology of disease. Standing in the way of such discoveries, however, is the fact that statistics for rare variants are currently designed for use with population-based data. In this paper, we introduce a pedigree-based statistic specifically designed to test for rare variants in family-based data. The additional power of pedigree-based statistics stems from the fact that while rare variants related to diseases or traits of interest occur only infrequently in populations, in families with multiple affected individuals, such variants are enriched. Note that while the proposed statistic can be applied with and without statistical weighting, our simulations show that its power increases when weighting (WSS and VT) are applied.ResultsOur working hypothesis was that, since rare variants are concentrated in families with multiple affected individuals, pedigree-based statistics should detect rare variants more powerfully than population-based statistics. To evaluate how well our new pedigree-based statistics perform in association studies, we develop a general framework for sequence-based association studies capable of handling data from pedigrees of various types and also from unrelated individuals. In short, we developed a procedure for transforming population-based statistics into tests for family-based associations. Furthermore, we modify two existing tests, the weighted sum-square test and the variable-threshold test, and apply both to our family-based collapsing methods. We demonstrate that the new family-based tests are more powerful than corresponding population-based test and they generate a reasonable type I error rate.To demonstrate feasibility, we apply the newly developed tests to a pedigree-based GWAS data set from the Framingham Heart Study (FHS). FHS-GWAS data contain approximately 5000 uncommon variants with frequencies less than 0.05. Potential association findings in these data demonstrate the feasibility of the software PB-STAR (note, PB-STAR is now freely available to the public).ConclusionOur tests show that when analyzing for rare variants, a pedigree-based design is more powerful than a population-based case-control design. We further demonstrate that a pedigree-based statistic's power to detect rare variants increases in direct relation to the proportion of affected individuals within the pedigree.

Dataset Information

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

Publications

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

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