A large-scale multi-ancestry mitochondrial variant association analysis for cardiometabolic traits

Area of Science:

• Genetics and Genomics
• Cardiovascular and Metabolic Diseases
• Mitochondrial Biology

Background:

• Mitochondrial DNA (mtDNA) studies for complex traits often face limitations due to small sample sizes and specific cohort selection.
• Understanding mtDNA's role in cardiometabolic diseases requires large-scale, multi-ancestry analyses.

Purpose of the Study:

• To investigate the association between mitochondrial DNA (mtDNA) variation and cardiometabolic phenotypes across diverse ancestral populations.
• To identify specific mtDNA variants and haplogroups linked to complex traits like type 2 diabetes and hypothyroidism.

Main Methods:

• Utilized data from over 600,000 participants in the Million Veteran Program (MVP) for a multi-ancestry analysis.
• Validated 248 mtDNA loci and performed ancestry-stratified, sex-stratified, and type 2 diabetes-stratified association analyses.
• Conducted gene-based rare-variant tests and analyzed associations with endocrine/metabolic categories.

Main Results:

• Identified 10 ancestry-stratified single-variant associations (8 European, 2 African) and 23 additional signals in sex- and type 2 diabetes-stratified analyses.
• Found four variants tagging haplogroup J associated with hypothyroidism in European populations, replicated in UK Biobank.
• Discovered associations between mitochondrial tRNA burdens and primary cardiomyopathy (females) and exophthalmos (males).

Conclusions:

• mtDNA variation contributes to cardiometabolic diseases in an ancestry- and context-specific manner.
• A significant enrichment of mtDNA associations was observed in endocrine and metabolic traits.
• The findings provide a framework for future mtDNA analyses in large biobank cohorts.