Autism and mtDNA?

A new study finds a link between mtDNA clades and autism prevalence. While there is a plausible biochemical mechanism by which this link could arise, based upon other work I've seen on inheritance patterns in autism, I'm quite skeptical of the result.

The current study analyzed these mtDNA lineages among 1,624 patients with autism and 2,417 healthy parents and siblings, representing 933 families in the Autism Genetic Resource Exchange (AGRE). Using data from genome-wide association studies on this AGRE cohort previously performed by the Center for Applied Genomics at CHOP, they determined patterns of functional mtDNA variants associated with ASD risk that emerged over human history. 

The study team found that individuals with European haplogroups designated I, J, K, O-X, T and U (representing 55 percent of the total European population) had significantly higher risks of ASD compared to the most common European haplogroup, HHV. Asian and Native American haplogroups A and M also were at increased risk of ASD. 

These findings support the idea that an individual already predisposed to ASD based on their mitochondrial haplogroup may develop the disease when additional genetic variants or environmental insults occur that lower mitochondrial function, impair OXPHOS, and alter brain activity.

Among the reasons to be skeptical: the p-value is only 0.04 so it looks like p-hacking by carefully choosing results bins after the fact; the sample size is exaggerated because the samples are not independent, the characterization of the mtDNA haplogroups involved is non-standard (mtDNA haplogroup O is Australian aboriginal, so a European haplogroup O-X makes no sense; there is no mtDNA haplogroup HHV and instead there are two separate ones H and HV); the odds ratios aren't huge; mtDNA clades are strongly ancestry informative and could be tracking differences in diagnosis rates or ancestry correlated autosomal traits; these are very broad categories that aren't phylogenically coherent.

More evidence of p-hacking in this paper flows from the fact that a 2013 study with a similar design and only modestly smaller sample size found no significant association between mtDNA haplogroup and autism risk and did not show the autism-mtDNA links for  any of the specific haplogroups reported on in the 2017 paper, despite having a similar, although moderately smaller sample size in terms of independent individuals (818 cases and 1641 controls). The abstract of that paper and its citation are as follows:

Despite the increasing speculation that oxidative stress and abnormal energy metabolism may play a role in Autism Spectrum Disorders (ASD), and the observation that patients with mitochondrial defects have symptoms consistent with ASD, there are no comprehensive published studies examining the role of mitochondrial variation in autism. Therefore, we have sought to comprehensively examine the role of mitochondrial DNA (mtDNA) variation with regard to ASD risk, employing a multi-phase approach. In phase 1 of our experiment, we examined 132 mtDNA single-nucleotide polymorphisms (SNPs) genotyped as part of our genome-wide association studies of ASD. In phase 2 we genotyped the major European mitochondrial haplogroup-defining variants within an expanded set of autism probands and controls. Finally in phase 3, we resequenced the entire mtDNA in a subset of our Caucasian samples (∼400 proband-father pairs). In each phase we tested whether mitochondrial variation showed evidence of association to ASD. Despite a thorough interrogation of mtDNA variation, we found no evidence to suggest a major role for mtDNA variation in ASD susceptibility. Accordingly, while there may be attractive biological hints suggesting the role of mitochondria in ASD our data indicate that mtDNA variation is not a major contributing factor to the development of ASD.

Hadjixenofontos, A, et al., "Evaluating mitochondrial DNA variation in autism spectrum disorders." 77(1) Ann Hum Genet. 9-21 (2013 epublished November 6, 2012) doi: 10.1111/j.1469-1809.2012.00736.x. (Open access).

Another lack of association between ASD and mtDNA variation was found in a 2011 study. The 2011 and 2013 studies combined have as large a sample size, if not larger, than the 2017 paper.

So, two of three studies have found a lack of association and the one that did find the association has a p value of 0.04 which is not statistically significant after considering look elsewhere effects given that at least three such studies have been done.

Background on sibling shared autism risk can be found here. All siblings with the same mother have the same mtDNA. The odds ratio for siblings of ASD affected individuals to have an ASD is 9.4-14.7 which is much greater than the odds ratio associated with sharing an mtDNA haplogroup.

Ideally, mtDNA associations would be studied at maximal sub-haplogroup detail, in light of a phylogeny of the haplogroups implicated, and excluding cases where a de novo mutation was likely such as in cases of advanced paternal age, as well as cases where a paternal inheritance was likely due to sub-clinical or clinical ASD symptoms in the father.

The abstract and citation to the new paper are as follows:

Importance Autism spectrum disorders (ASD) are characterized by impairments in social interaction, communication, and repetitive or restrictive behavior. Although multiple physiologic and biochemical studies have reported defects in mitochondrial oxidative phosphorylation in patients with ASD, the role of mitochondrial DNA (mtDNA) variation has remained relatively unexplored. 

Objective To assess what impact mitochondrial lineages encompassing ancient mtDNA functional polymorphisms, termed haplogroups, have on ASD risk. 

Design, Setting, and Participants In this cohort study, individuals with autism and their families were studied using the Autism Genetic Resource Exchange cohort genome-wide association studies data previously generated at the Children’s Hospital of Philadelphia. From October 2010 to January 2017, we analyzed the data and used the mtDNA single-nucleotide polymorphisms interrogated by the Illumina HumanHap 550 chip to determine the mtDNA haplogroups of the individuals. Taking into account the familial structure of the Autism Genetic Resource Exchange data, we then determined whether the mtDNA haplogroups correlate with ASD risk. 

Main Outcomes and Measures Odds ratios of mitochondrial haplogroup as predictors of ASD risk. 

Results Of 1624 patients with autism included in this study, 1299 were boys (80%) and 325 were girls (20%). Families in the Autism Genetic Resource Exchange collection (933 families, encompassing 4041 individuals: 1624 patients with ASD and 2417 healthy parents and siblings) had been previously recruited in the United States with no restrictions on age, sex, race/ethnicity, or socioeconomic status. Relative to the most common European haplogroup HHV, European haplogroups I, J, K, O-X, T, and U were associated with increased risk of ASD, as were Asian and Native American haplogroups A and M, with odds ratios ranging from 1.55 (95% CI, 1.16-2.06) to 2.18 (95% CI, 1.59-3) (adjusted P < .04). Hence, mtDNA haplogroup variation is an important risk factor for ASD. 

Conclusions and Relevance Because haplogroups I, J, K, O-X, T, and U encompass 55% of the European population, mtDNA lineages must make a significant contribution to overall ASD risk.

Dimitra Chalkia, et al., "Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders" JAMA Psychiatry. (Published online August 23, 2017). doi:10.1001/jamapsychiatry.2017.2604