New genetic candidates help explain why autism affects males more often than females

Researchers at Baylor College of Medicine and collaborating institutions have identified genetic factors that may explain why autism spectrum disorder (ASD) is diagnosed four times more often in boys than girls. The study, published in the American Journal of Human Genetics, suggests that subtle changes in the MECP2 gene located on the X chromosome may contribute to this sex-specific vulnerability.

Autism is a heritable neurodevelopmental condition characterized by difficulties in social interaction, communication, and the presence of repetitive behaviors or interests. Dr. Huda Zoghbi, corresponding author of the study, explained that the higher rate of ASD diagnosis in males implies that certain factors may predispose males to the condition more frequently.

The researchers focused on the MECP2 gene due to its association with neurodevelopmental conditions and its role in brain health. In males, who possess only one copy of the X chromosome, mutations in the MECP2 gene can be more detrimental than in females, who have two X chromosomes. Dr. Rebecca Meyer-Schuman, first author of the study, stated that this is because females have a backup copy of the gene, which can mitigate the impact of a single copy mutation.

The researchers utilized a laboratory tool called massively parallel reporter assay (MPRA) to screen the regulatory regions of the MECP2 gene. This technique allowed them to identify and manipulate these regions to determine how changes in their function could impact MECP2 expression. They also screened MECP2 regulatory regions in autistic individuals and analyzed the genetic variants they discovered using MPRA assays.

The study found two regulatory regions where male autistic individuals inherited a variant from their unaffected mother, which altered MECP2 expression. One of these variants reduced MECP2 expression by approximately 30% in human neurons, a level that produces social deficits, hyperactivity, and anxiety-like characteristics in mice.

This variant was found in individuals diagnosed with autism and ADHD but did not result in the defining characteristics of Rett syndrome, a neurodevelopmental disorder also linked to MECP2 mutations.

The findings of this study, which combined human and animal research, suggest that MECP2 regulatory variants can contribute to male-biased autism. The results provide a framework for identifying additional regulatory variants in other X chromosome neurodevelopmental genes that may contribute to the "missing heritability" of autism.