Network analysis of mitonuclear GWAS reveals functional networks and tissue expression profiles of disease-associated genes

Hum Genet. 2017 Jan;136(1):55-65. doi: 10.1007/s00439-016-1736-9. Epub 2016 Oct 4.


While mitochondria have been linked to many human diseases through genetic association and functional studies, the precise role of mitochondria in specific pathologies, such as cardiovascular, neurodegenerative, and metabolic diseases, is often unclear. Here, we take advantage of the catalog of human genome-wide associations, whole-genome tissue expression and expression quantitative trait loci datasets, and annotated mitochondrial proteome databases to examine the role of common genetic variation in mitonuclear genes in human disease. Through pathway-based analysis we identified distinct functional pathways and tissue expression profiles associated with each of the major human diseases. Among our most striking findings, we observe that mitonuclear genes associated with cancer are broadly expressed among human tissues and largely represent one functional process, intrinsic apoptosis, while mitonuclear genes associated with other diseases, such as neurodegenerative and metabolic diseases, show tissue-specific expression profiles and are associated with unique functional pathways. These results provide new insight into human diseases using unbiased genome-wide approaches.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Cardiovascular Diseases / genetics
  • Cell Nucleus / genetics
  • DNA, Mitochondrial / genetics
  • Gene Ontology
  • Gene Regulatory Networks*
  • Genetic Predisposition to Disease / genetics*
  • Genome, Human*
  • Genome-Wide Association Study*
  • Humans
  • Inflammation / genetics
  • Metabolic Diseases / genetics
  • Neoplasms / genetics
  • Neurodegenerative Diseases / genetics
  • Organ Specificity
  • Polymorphism, Single Nucleotide
  • Protein Interaction Mapping
  • Quantitative Trait Loci
  • Sequence Analysis, RNA
  • Transcriptome


  • DNA, Mitochondrial