Family-based mitochondrial association study of traits related to type 2 diabetes and the metabolic syndrome in adolescents

Abstract

Aims/hypothesis There has been much focus on the potential role of mitochondria in the aetiology of type 2 diabetes and the metabolic syndrome, and many casecontrol mitochondrial association studies have been undertaken for these conditions. We tested for a potential association between common mitochondrial variants and a number of quantitative traits related to type 2 diabetes in a large sample of >2,000 healthy Australian adolescent twins and their siblings, many of whom were measured on more than one occasion. Methods To the best of our knowledge, this is the first mitochondrial association study of quantitative traits undertaken using family data. The maternal inheritance pattern of mitochondria means established association methodologies are unsuitable for analysis of mitochondrial data in families. We present a methodology, implemented in the freely available program Sib-Pair for performing such an analysis.Results Despite our study having the power to detect variants with modest effects on these phenotypes, only one significant association was found after correction for multiple testing in any of four age groups. This was for mt14365 with triacylglycerol levels (unadjusted p=0.0006). This association was not replicated in other age groups. Conclusions/interpretation We find little evidence in our sample to suggest that common European mitochondrial variants contribute to variation in quantitative phenotypes related to diabetes. Only one variant showed a significant association in our sample, and this association will need to be replicated in a larger cohort. Such replication studies or future meta-analyses may reveal more subtle effects that could not be detected here because of limitations of sample size.

Family History of Hypertension and Cardiovascular Risk Factors in Prepubertal Children

“…These findings suggest that the history of maternal hypertension indicates greater cardiovascular risk in children. [26][27][28][29][30] Furthermore, these findings support the hypothesis that cardiovascular risk phenotype is transmitted on the maternal lineage with a pattern that indicates mitochondrial DNA-mediated inheritance. Although a body of evidence has accumulated in this regard, further research is needed to give new insight to the genetic etiology of cardiovascular risk in children.…”

Association of Genetic Variation in the Mitochondrial Genome With Blood Pressure and Metabolic Traits

“…Replication of our results in independent study samples is warranted, although very large sample sizes are required to identify associations with such low frequency (0.4% - 0.6%) variants. Inadequate sample sizes and the focus on common mtDNA polymorphisms and major haplogroups may explain the failure of earlier population-based association studies to identify an association of mtDNA variants with BP and metabolic traits 35, 55, 56 . Advances in sequencing may facilitate the identification of rare mitochondrial variants in additional large study cohorts and allow replication of our findings in the near future.…”

Deep sequencing of the mitochondrial genome reveals common heteroplasmic sites in NADH dehydrogenase genes

“…1,4,12–18 Replication of associations between homoplasmic mtDNA mutations and common diseases has proven difficult due to small sample sizes in previous studies or lack of replication samples. 15–17 Establishing the role of heteroplasmic mtDNA variation in relation to complex phenotypes is still in its infancy and the genetic basis for the age-related decline in mitochondrial function remains unclear. 19,20 With the advent of next generation sequencing and reduced costs of whole-genome sequencing, it is now possible to study a spectrum of rare/low-frequency and heteroplasmic mtDNA variants in large sample sizes.…”