Investigating the relationship between mitochondrial genetic variation and cardiovascular-related traits to develop a framework for mitochondrial phenome-wide association studies.

Sabrina L Mitchell,Jacob B Hall,Eric Farber-Eger,Jonathan Boston,Sarah A Pendergrass,William S Bush,Dana C Crawford,Robert J Goodloe

doi:10.1186/1756-0381-7-6

Abstract

BackgroundMitochondria play a critical role in the cell and have DNA independent of the nuclear genome. There is much evidence that mitochondrial DNA (mtDNA) variation plays a role in human health and disease, however, this area of investigation has lagged behind research into the role of nuclear genetic variation on complex traits and phenotypic outcomes. Phenome-wide association studies (PheWAS) investigate the association between a wide range of traits and genetic variation. To date, this approach has not been used to investigate the relationship between mtDNA variants and phenotypic variation. Herein, we describe the development of a PheWAS framework for mtDNA variants (mt-PheWAS). Using the Metabochip custom genotyping array, nuclear and mitochondrial DNA variants were genotyped in 11,519 African Americans from the Vanderbilt University biorepository, BioVU. We employed both polygenic modeling and association testing with mitochondrial single nucleotide polymorphisms (mtSNPs) to explore the relationship between mtDNA variants and a group of eight cardiovascular-related traits obtained from de-identified electronic medical records within BioVU.ResultsUsing polygenic modeling we found evidence for an effect of mtDNA variation on total cholesterol and type 2 diabetes (T2D). After performing comprehensive mitochondrial single SNP associations, we identified an increased number of single mtSNP associations with total cholesterol and T2D compared to the other phenotypes examined, which did not have more significantly associated SNPs than would be expected by chance. Among the mtSNPs significantly associated with T2D we identified variant mt16189, an association previously reported only in Asian and European-descent populations.ConclusionsOur replication of previous findings and identification of novel associations from this initial study suggest that our mt-PheWAS approach is robust for investigating the relationship between mitochondrial genetic variation and a range of phenotypes, providing a framework for future mt-PheWAS.

Highlights

Mitochondria play a critical role in the cell and have Deoxyribonucleic acid (DNA) independent of the nuclear genome
We found that total cholesterol and type 2 diabetes (T2D), which exhibited the most evidence for a contribution of mitochondrial genetic variation to trait variance or risk, had the highest number of significantly associated Mitochondrial single nucleotide polymorphism (mtSNP)
In the present study we identified 13 mitochondrial DNA (mtDNA) Single nucleotide polymorphism (SNP) associated with T2D in African Americans including variant mt16189, which was previously shown to be correlated with fasting insulin concentration [25], fasting glucose, and body mass index (BMI) [26], and has been associated with T2D in both Asian [27] and European-descent populations [28]

Summary

Introduction

Mitochondria play a critical role in the cell and have DNA independent of the nuclear genome. There is much evidence that mitochondrial DNA (mtDNA) variation plays a role in human health and disease, this area of investigation has lagged behind research into the role of nuclear genetic variation on complex traits and phenotypic outcomes. Using the Metabochip custom genotyping array, nuclear and mitochondrial DNA variants were genotyped in 11,519 African Americans from the Vanderbilt University biorepository, BioVU We employed both polygenic modeling and association testing with mitochondrial single nucleotide polymorphisms (mtSNPs) to explore the relationship between mtDNA variants and a group of eight cardiovascular-related traits obtained from de-identified electronic medical records within BioVU. Mitochondrial dysfunction has been observed in a variety of diseases, including amyotrophic lateral sclerosis (ALS), Huntington’s disease, Alzheimer’s disease, and various types of cancer [1] Mitochondria maintain their own DNA separate from the nuclear genome. The range of phenotypes associated with mtDNA variation underscores the pleiotropic nature of mitochondrial genetic variation

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