Autism spectrum disorder is more prevalent among males than females, with studies frequently reporting a 2:1 or 3:1 male to female bias. While the causes of this bias are still unknown, a series of new studies have revealed new insights into how the different genders affect the condition.

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A 2:1 or 3:1 male to female autism spectrum disorder prevalence bias is frequently reported in studies.

The series is published in Molecular Autism and explores structural differences in the brain, the role of prenatal sex hormones and a theory referred to as the “female protective effect.”

“Autism has always been perceived as a condition that occurs more often in males, which means that females are usually underrepresented in research studies,” explains guest editor Meng-Chuan Lai from the University of Cambridge, UK. “This means there’s a risk that the scientific and clinical literature provides a partial, male-based understanding of autism.”

It is clear, however, that autism spectrum disorder (ASD) is not simply a male condition. “Delineating the role that sex and gender play in the characteristics of autism, across multiple levels, may inform both our ability to identify the condition and lead to a greater understanding of its developmental psychology and biology,” says Dr. Lai.

One study identified significant structural differences in the brains of male toddlers with ASD compared with female toddlers with the same condition. Researchers from the MIND Institute at the University of California, Davis, examined the organization of fibers in the corpus callosum in the brains of 139 children with autism and 82 typically developing children.

All the children with ASD had alterations in the areas of corpus callosum connected with to their frontal lobes. The nature of these alterations differed between male children and female children, however.

While the male children had smaller callosal regions connecting the part of the brain associated with emotional processing and reward-related decision-making, the female children had smaller callosal regions connecting to the part of the brain involved in higher order executive functioning.

Another difference in the brains of males and females was revealed in a study conducted by researchers at George Washington University, DC. The study investigated the levels of the gene RORA, known to regulate several genes connected to autism, in the brains of typically developing males and females.

Experts have previously proposed RORA deficiency as a factor that could increase the male risk factor of ASD. In the study, the researchers found that RORA protein levels were higher in the brains of typically developing females in comparison with typically developing males, suggesting that females are less likely to have RORA deficiency.

This finding may tie into the theory of the female protective effect – the idea that there is a mechanism in the female brain that protects it from developing ASD. Two other studies in the series explore this theory further.

In the first, conducted by researchers at the University of California, Los Angeles, analyzed ASD risk in over 1,120 families, specifically investigating the rate at which ASD developed in siblings and how this differed between males and females.

Under the female protective effect model, females with ASD are believed to carry a greater genetic load than males that predisposes them to the condition. Furthermore, this greater genetic liability is believed to be shared with their siblings.

The researchers examined the rate of ASD recurrence in the children of families with at least one female family member with ASD compared with families who only have male members with ASD. A significantly greater risk of ASD was observed among siblings of females with ASD compared with siblings of males with ASD.

Higher recurrence of ASD was also found in males in all families, suggesting to the authors that female protective mechanisms are still operative in families carrying higher genetic risk loads.

The final study involved an analysis of genetic data from more than 4,500 families affected by ASD. This research was led by scientists at Washington University, St. Louis, the University of California, San Francisco, and Yale School of Medicine. The team found that no single gene is associated with the female protective effect, suggesting that multiple genes may be behind the mechanism.

“A focus on sex and gender in autism research should help improve the clinical identification of females who may have autism that has gone undiagnosed,” writes Simon Baron-Cohen, co-editor in chief of Molecular Autism.

“Research into this topic may also help us understand the complex mix of sex-linked genetic, hormonal, and social factors that contribute to individual differences in social and language development and flexible adaptation to change, as well as autism itself.”