Mitochondrial DNA copy number as a phenotypic trait for human diseases in genetic epidemiological studies

Cells contain elements called mitochondria. Mitochondria contain their own DNA (mtDNA). Variation in this DNA is related to disease. Diseases influenced by mtDNA include obesity, diabetes and hyperlipidemia. However, two aspects of mtDNA are underexplored. The first aspect is the analysis of the number of copies of mtDNA present in cells in relation to human health traits. The second aspect is to study whether the
number of copies of mtDNA is determined by nuclear genes. Our project aims to study whether the number of copies of mtDNA associate with traits related to obesity, diabetes, hyperlipidemia and cognitive function. We also aim to identify nuclear genes controlling the number of copies of mtDNA. To this end, we will determine the number of copies of mtDNA in each of the 20,000 individuals of one population sample (Avon Longitudinal Study of Parents and Children, ALSPAC). The results from this project would contribute to the study of obesity, diabetes, hyperlipidemia and cognitive risk traits. This would represent new knowledge and potential benefit for improving human health.

Mitochondrial DNA (mtDNA) has been studied in relation to population genetics and human disease. Mutations and depletion of mtDNA have been related to a variety of diseases. There is evidence suggesting that depletion of mtDNA is associated with metabolic disorders such as obesity, diabetes and hyperlipidemia. However, variation of mtDNA copy number as a continuous trait in relation to genetic epidemiological studies is underexplored. The same applies to the study of nuclear genes exerting control in the genetic variation of mtDNA. Our aims here are i) to conduct association studies between mtDNA copy number and complex traits including adiposity, fasting glucose, insulin, lipids and cognitive function, aiming to identify relations between mtDNA copy number and these traits relevant to disease; and ii) to conduct a genomewide association scan (GWAS) aiming to identify nuclear genes controlling mtDNA copy number. To this end, we will determine mtDNA copy number in an established and densely phenotyped cohort (Avon Longitudinal Study of Parents and Children, ALSPAC, N = 20,000). The results from this project would open a new dimension on the study of obesity, diabetes, hyperlipidemia and cognitive risk traits, representing new basic knowledge and potential benefit for improving human health. If we demonstrate that mtDNA copy number can be used as a biomarker for obesity, diabetes, hyperlipidemia and cognitive risk traits, its use could also be applied to the study of other diseases.

This research will have social and economic impact in the following ways:

Health Research - Obesity, diabetes and hyperlipidemia are diseases with major impact on human health. This proposal will establish whether mtDNA copy number can be used as a blood biomarker in relation to these health phenotypes. If so, its use could enable medical interventions dependent on mtDNA copy number genotype.

Economy and society - Obesity and diabetes have are a major health burden in the UK and developed world, and they are leading causes of working days lost and premature death. Early diagnosis of obesity and diabetes will reduce the costs associated with the care of patients with these conditions. It will also reduce the mortality and morbidity of these common diseases.

Training - The post doctoral research fellow undertaking this work will benefit from developing skills and expertise in different but related areas of research. These include experimental lab work and statistical genetic analysis such as genomewide association mapping and Mendelian Randomization.

Public Understanding of science. The general public have a substantial interest in genetic causes of disease, and in particular in research that underpins our understanding of the development of disease and new scientific discoveries in the detection, characterisation, prevention and treatment of disease. We will communicate research of interest through public outreach activities and press releases.