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Altered Mitochondria Associated With Increased Autism Risk

Summary: A new study reports mitochondrial changesmay be important risk factors for identifying those with autism spectrum disorders.

Source: Children’s Hospital of Philadelphia.

Ancient mitochondrial DNA genetic patterns may play role in this neurodevelopmental condition.

Mitochondria, the tiny structures inside our cells that generate energy, may play a key role in autism spectrum disorders (ASD). A provocative new study by Children’s Hospital of Philadelphia (CHOP)’s pioneering mitochondrial medicine team suggests that variations in mitochondrial DNA (mtDNA) originating during ancient human migrations may play an important role in predisposition to ASDs.

“Our findings show that differences in mitochondrial function are important in ASD,” said study leader Douglas C. Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine at CHOP. “Our team demonstrates that a person’s vulnerability to ASD varies according to their ancient mitochondrial lineage.”

Wallace and colleagues, including Dimitra Chalkia, Larry Singh and others, published their findings today in JAMA Psychiatry.

The scientists conducted a cohort study of genetic data from 1,624 patients and 2,417 healthy parents and siblings, representing 933 families in the Autism Genetic Resource Exchange (AGRE). The Center for Applied Genomics at CHOP had previously performed genome-wide association studies on this AGRE cohort, and partnered in this study.

Mitochondria contain their own DNA, distinct from the more familiar nuclear DNA (nDNA) inside the cell nucleus. The mtDNA codes for essential genes governing cellular energy production, and those genes exchange biological signals with nDNA to affect our physiology and overall health.

The current study analyzed single-nucleotide functional variants–base changes in the cohort’s mtDNA that characterize mitochondrial haplogroups. Haplogroups are lineages of associated mtDNA variants that reflect the ancient migration patterns of early human bands that spread out of Africa to the rest of the world during prehistory. Based on his seminal 1980 discovery that the human mtDNA is inherited only through the mother, Wallace’s surveys over the years, covering mtDNA variation among indigenous populations around the world, have permitted the reconstruction of human worldwide migrations and evolution patterns over hundreds of millennia.

The current study found that individuals with European haplogroups designated I, J, K, 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 mitochondrial haplogroups originated in different global geographic areas, adapted through evolution to specific regional environments. However, subsequent changes, such as migration, changes in diet, and other environmental influences, can create a mismatch between the physiology of a particular mtDNA lineage and the individual’s environment, resulting in predisposition to disease. Additional nDNA genetic factors or environmental insults may further reduce an individual’s energy output until it is insufficient to sustain normal brain development and function, resulting in disease.

As the wiring diagram for cellular power plants, mtDNA is crucial in supplying energy to the body. The brain is particularly vulnerable to even mild energy deficiencies because of its high mitochondrial energy demand. Wallace’s previous studies have shown that mitochondrial dysfunction can disturb the delicate balance between inhibition and excitation in brain activity–a crucial factor in ASDs and other neuropsychiatric disorders. “There may be a bioenergetic threshold,” says Wallace, adding that an individual already predisposed to ASD based on their mitochondrial haplogroup may be pushed below that threshold by the chance occurrence of additional genetic variants or environmental insults.

mitochondria.

Mitochondria contain their own DNA, distinct from the more familiar nuclear DNA (nDNA) inside the cell nucleus. The mtDNA codes for essential genes governing cellular energy production, and those genes exchange biological signals with nDNA to affect our physiology and overall health. NeuroscienceNews.com image is in the public domain.

The striking tendency for ASD to occur more frequently in males than females may reflect another peculiarity of mitochondrial genetics, added Wallace. Males are four times more likely to suffer blindness from a well-known mtDNA disease, Leber hereditary optic neuropathy (LHON). The lower risk of blindness in females may arise from estrogen effects in mitochondria that increase beneficial antioxidant activity.

Wallace said that his team’s finding that subtle changes in mitochondrial energetics are important risk factors in ASD suggests potential alternative approaches for therapy. He added, “There is increasing interest in developing metabolic treatments for known mtDNA diseases such as LHON. If ASD has a similar etiology, then these same therapeutic approaches may prove beneficial for ASD.”

About this neuroscience research article

Funding: The National Institutes of Health (grants MH108592, NS021328, and NS070298) and the Simons Foundation supported this study. In addition to his CHOP position, Wallace is on the faculty of the Perelman School of Medicine at the University of Pennsylvania.

Source: Camillia Travia – Children’s Hospital of Philadelphia
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders” by Dimitra Chalkia, PhD; Larry N. Singh, PhD; Jeremy Leipzig, MS; Maria Lvova, MD; Olga Derbeneva, PhD; Anita Lakatos, PhD; Dexter Hadley, PhD; Hakon Hakonarson, MD, PhD; Douglas C. Wallace, PhD in JAMA Psychiatry. Published online August 23 2017 doi:10.1001/jamapsychiatry.2017.2604

Cite This NeuroscienceNews.com Article
Children’s Hospital of Philadelphia “Altered Mitochondria Associated With Increased Autism Risk.” NeuroscienceNews. NeuroscienceNews, 23 August 2017.
<http://neurosciencenews.com/autism-mitochondria-7361/>.
Children’s Hospital of Philadelphia (2017, August 23). Altered Mitochondria Associated With Increased Autism Risk. NeuroscienceNew. Retrieved August 23, 2017 from http://neurosciencenews.com/autism-mitochondria-7361/
Children’s Hospital of Philadelphia “Altered Mitochondria Associated With Increased Autism Risk.” http://neurosciencenews.com/autism-mitochondria-7361/ (accessed August 23, 2017).

Abstract

Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders

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.

“Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders” by Dimitra Chalkia, PhD; Larry N. Singh, PhD; Jeremy Leipzig, MS; Maria Lvova, MD; Olga Derbeneva, PhD; Anita Lakatos, PhD; Dexter Hadley, PhD; Hakon Hakonarson, MD, PhD; Douglas C. Wallace, PhD in JAMA Psychiatry. Published online August 23 2017 doi:10.1001/jamapsychiatry.2017.2604

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