Dataset Information

Association testing of the mitochondrial genome using pedigree data.

ABSTRACT: In humans, mitochondria contain their own DNA (mtDNA) that is inherited exclusively from the mother. The mitochondrial genome encodes 13 polypeptides that are components of oxidative phosphorylation to produce energy. Any disruption in these genes might interfere with energy production and thus contribute to metabolic derangement. Mitochondria also regulate several important cellular activities including cell death and calcium homeostasis. Aided by sharply declining costs of high-density genotyping, hundreds of mitochondrial variants will soon be available in several cohorts with pedigree structures. Association testing of mitochondrial variants with disease traits using pedigree data raises unique challenges because of the difficulty in separating the effects of nuclear and mitochondrial genomes, which display different modes of inheritance. Failing to correctly account for these effects might decrease power or inflate type I error in association tests. In this report, we sought to identify the best strategy for association testing of mitochondrial variants when genotype and phenotype data are available in pedigrees. We proposed several strategies to account for polygenic effects of the nuclear and mitochondrial genomes and we performed extensive simulation studies to evaluate type I error and power of these strategies. In addition, we proposed two permutation tests to obtain empirical P values for these strategies. Furthermore, we applied two of the analytical strategies to association analysis of 196 mitochondrial variants with blood pressure and fasting blood glucose in the pedigree rich, Framingham Heart Study. Finally, we discussed strategies for study design, genotyping, and data cleaning in association testing of mtDNA in pedigrees.

SUBMITTER: Liu C

PROVIDER: S-EPMC4171957 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Association testing of the mitochondrial genome using pedigree data.

Liu Chunyu C Dupuis Josée J Larson Martin G MG Levy Daniel D

Genetic epidemiology 20130114 3

In humans, mitochondria contain their own DNA (mtDNA) that is inherited exclusively from the mother. The mitochondrial genome encodes 13 polypeptides that are components of oxidative phosphorylation to produce energy. Any disruption in these genes might interfere with energy production and thus contribute to metabolic derangement. Mitochondria also regulate several important cellular activities including cell death and calcium homeostasis. Aided by sharply declining costs of high-density genotyp ...[more]

PMID: 23319385

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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.

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Association testing of the mitochondrial genome using pedigree data.

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Association testing of the mitochondrial genome using pedigree data.

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