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August 24, 2017

'Provocative' CHOP study identifies new potential risk factor for autism

A "provocative" study led by genetic researchers at the Children's Hospital of Philadelphia claims that heightened risk for autism spectrum disorder may be influenced by mitochondrial evolution in our ancient ancestors.

Led by CHOP's mitochondrial medicine team, the study published in JAMA Psychiatry suggests migratory changes in mitochondrial DNA (mtDNA) — the code for genes governing cellular energy production — could be associated with higher rates of autism in several European, Asian and Native American lineages.

Study leader Douglas C. Wallace, director of CHOP's Center for Mitochondrial and Epigenomic Medicine, built the current findings on decades of research into mtDNA variation among indigenous groups and ancient migratory populations.

Wallace is credited with the groundbreaking 1980 discovery that mtDNA is only transmitted by the mother. Much of his research since then has since worked to sharpen our genetic understanding of mitochondrial haplogroups—the various lineages associated with mtDNA variants from prehistoric diasporas. These relocations can result in evolutionary mismatches between physiology and environment.

“Our findings show that differences in mitochondrial function are important in ASD,” said Wallace. "Our team demonstrates that a person’s vulnerability to ASD varies according to their ancient mitochondrial lineage.”

Distinct from nuclear DNA, mtDNA plays a crucial role in supplying energy to the brain. Even mild deficiencies in mitochondrial energy can lead to dysfunction, upsetting the brain's balance between inhibition and excitation, according to the study authors. If compounded by other nuclear DNA and environmental factors, these disturbances can lead to ASD's and other neuropsychiatric disorders.

“There may be a bioenergetic threshold,” Wallace said.

For the current study, Wallace's team looked at mtDNA variants in single nucleotides that categorize particular mitochondrial haplogroups. They analyzed a cohort study of genetic data from 1,624 patients and 2,417 healthy parents and siblings, a group representing 933 families in the Autism Genetic Resource Exchange.

A full 55 percent of haplogroups from Europe had a significantly higher risk of ASD compared to those from the most common European haplogroup, according to the CHOP's teams findings, while a pair of Asian and Native American haplogroups were also found to be at higher risk.

Wallace points to the higher prevalence of ASD in males as supporting evidence of a mitochondrial link. Men are also four times more likely to suffer from Leber hereditary optic neuropathy (LHON), an mtDNA disease that causes blindness.

The study, supported by the National Institutes of Health and the Simons Foundation, hopes to promote research into alternative therapeutic approaches to ASD.

“There is increasing interest in developing metabolic treatments for known mtDNA diseases such as LHON," Wallace said. "If ASD has a similar etiology, then these same therapeutic approaches may prove beneficial for ASD.”

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