Association of mitochondrial DNA content, heteroplasmies and inter-generational transmission with autism

Mitochondria are essential for brain development. While previous studies linked dysfunctional mitochondria with autism spectrum disorder (ASD), the role of the mitochondrial genome (mtDNA) in ASD risk is largely unexplored. This study investigates the association of mtDNA heteroplasmies (co-existence of mutated and unmutated mtDNA) and content with ASD, as well as its inter-generational transmission and sex differences among two independent samples: a family-based study ( n = 1,938 families with parents, probands and sibling controls) and a prospective birth cohort ( n = 997 mother-child pairs). In both samples, predicted pathogenic (PP) heteroplasmies in children are associated with ASD risk (Meta-OR = 1.56, P = 0.00068). Inter-generational transmission of mtDNA reveals attenuated effects of purifying selection on maternal heteroplasmies in children with ASD relative to controls, particularly among males. Among children with ASD and PP heteroplasmies, increased mtDNA content shows benefits for cognition, communication, and behaviors ( P ≤ 0.02). These results underscore the value of exploring maternal and newborn mtDNA in ASD. Most genetic studies of autism spectrum disorder (ASD) have focused on the nuclear genome. Here, the authors show that variations in mitochondrial DNA, detectable at birth, are also associated with risk of ASD.