Genetic Evidence for Elevated Pathogenicity of Mitochondrial DNA Heteroplasmy in Autism Spectrum Disorder

PLoS Genet. 2016 Oct 28;12(10):e1006391. doi: 10.1371/journal.pgen.1006391. eCollection 2016 Oct.

Abstract

Increasing clinical and biochemical evidence implicate mitochondrial dysfunction in the pathophysiology of Autism Spectrum Disorder (ASD), but little is known about the biological basis for this connection. A possible cause of ASD is the genetic variation in the mitochondrial DNA (mtDNA) sequence, which has yet to be thoroughly investigated in large genomic studies of ASD. Here we evaluated mtDNA variation, including the mixture of different mtDNA molecules in the same individual (i.e., heteroplasmy), using whole-exome sequencing data from mother-proband-sibling trios from simplex families (n = 903) where only one child is affected by ASD. We found that heteroplasmic mutations in autistic probands were enriched at non-polymorphic mtDNA sites (P = 0.0015), which were more likely to confer deleterious effects than heteroplasmies at polymorphic mtDNA sites. Accordingly, we observed a ~1.5-fold enrichment of nonsynonymous mutations (P = 0.0028) as well as a ~2.2-fold enrichment of predicted pathogenic mutations (P = 0.0016) in autistic probands compared to their non-autistic siblings. Both nonsynonymous and predicted pathogenic mutations private to probands conferred increased risk of ASD (Odds Ratio, OR[95% CI] = 1.87[1.14-3.11] and 2.55[1.26-5.51], respectively), and their influence on ASD was most pronounced in families with probands showing diminished IQ and/or impaired social behavior compared to their non-autistic siblings. We also showed that the genetic transmission pattern of mtDNA heteroplasmies with high pathogenic potential differed between mother-autistic proband pairs and mother-sibling pairs, implicating developmental and possibly in utero contributions. Taken together, our genetic findings substantiate pathogenic mtDNA mutations as a potential cause for ASD and synergize with recent work calling attention to their unique metabolic phenotypes for diagnosis and treatment of children with ASD.

MeSH terms

  • Adolescent
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / pathology
  • Child
  • DNA Mutational Analysis
  • DNA, Mitochondrial / genetics*
  • Exome / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Mitochondria / genetics*
  • Mitochondria / pathology
  • Mutation
  • Pedigree
  • Phenotype
  • Siblings

Substances

  • DNA, Mitochondrial

Grant support

This work was supported by various funds from Cornell University, NSF MCB-1243588, NIH 1R01AI085286, and a grant for ENN science and technology development to ZG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.