Examination of Mitochondrial Variation in Autism

Background: There has been increasing speculation that oxidative stress and abnormal energy metabolism may play a role in ASD (Autism Spectrum Disorders). It is essential that we begin to thoroughly identify and characterize the role of genes involved in oxidative stress, both those that reside in the mitochondria and those that are encoded in the nuclear genome. Of note there has been a profound lack of investigation into the role of mitochondrial variation in autism, despite numerous clinical reports describing patients with mitochondrial disorders or mutations who have symptoms consistent with ASD.  Further, mitochondrial inheritance would be consistent with the observed increase in neuropsychological abnormalities in the mothers of ASD children.

Objectives: To comprehensively examine the role of mitochondrial variation and nuclear-encoded mitochondrial gene variation with regard to autistic risk.

Methods: We have resequenced a discovery dataset of ~200 Caucasian proband-father pairs (181 probands/185 fathers) using the Affymetrix Human Mito2.0 chip. We are examining haplogroups, characterizing both common and rare mitochondrial variations, and testing for association of both haplogroups and mitochondrial variation with ASDs. Additionally, we are utilizing genome-wide single nucleotide polymorphism data generated from the Illumina 1-M beadchip on all individuals to test for gene x gene interactions between mitochondrial variations and nuclear-encoded mitochondrial gene variations. A validation dataset of ~200 proband-father pairs is also being sequenced.

Results: A number of single-nucleotide polymorphisms (SNPs) within the nuclear-encoded genes demonstrate modest association in our recent GWAS study. We have initially examined European-Caucasian haplogroups and haplogroup defining single-nucleotide polymorphisms (SNPs) to assess the odds of carrying each mitochondrial haplogroup/ or haplogroup defining SNP in Autism probands compared to unaffected fathers. These preliminary results suggest that the A allele at mtDNA position 10398 is significantly (p= 0.007) overrepresented in autism probands compared to their unaffected fathers.

Conclusions: These data will yield insight into mitochondrial variation on a level never before performed in autism. Furthermore, this unique project will begin to examine the role oxidative stress genes may play in ASDs.