Mitochondrial DNA (mtDNA) sequence variations have been causally implicated in cardiometabolic diseases (CMDs). However, the mechanisms linking mtDNA mutations to CMDs are not fully elucidated. Each human cell contains as many as 10,000 copies of mtDNA. As a result, there are two types of mtDNA mutations ? homoplasmic and heteroplasmic mutations. The latter represent the coexistence of two (or more) mtDNA alleles in the same cell or across cells. For most heteroplasmic mtDNA mutations, the proportion of mutant alleles is low and can only be detected by deep sequencing of mtDNA. Whole genome sequencing (WGS) through NHLBI?s Trans-Omics for Precision Medicine program has generated deep WGS data, including mtDNA, in tens of thousands of individuals, offering an unprecedented opportunity to investigate heteroplasmic mtDNA mutations in relation to CMDs. We propose to develop rigorous methods and a software suite to facilitate association studies of heteroplasmic mtDNA mutations in large samples. The novel methods and the software suite will be open source and available to the broad scientific community to study mtDNA sequence variation with respect to age-related diseases, including CMDs. The body of knowledge generated by these future findings will facilitate the development of new modalities for the diagnosis, prevention, and treatment of age-related diseases.

Public Health Relevance

Mitochondrial DNA (mtDNA) sequence variations have been causally implicated in cardiometabolic diseases (CMDs). We propose to develop rigorous methods and a software suite to facilitate association studies of heteroplasmic mtDNA mutations in large samples. The novel methods and the software suite will be open source and available to the broad scientific community to study mtDNA sequence variation in relation to a wide range of human diseases including CMDs, and thus, will greatly advance our understanding of the contributions of mtDNA mutations to human diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL144877-01
Application #
9647536
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Papanicolaou, George
Project Start
2019-02-04
Project End
2021-01-31
Budget Start
2019-02-04
Budget End
2020-01-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston University
Department
Biostatistics & Other Math Sci
Type
Schools of Public Health
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118