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New insights into the male bias of autism

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Male toddlers with autism have significant structural differences in their brains compared to females with the condition, according to research published in the open access journal Molecular Autism.

The journal is publishing a special series of articles looking at the links between sex/gender and autism, which reveal additional insights into the role of prenatal sex hormones and the 'female protective effect'.

Autism spectrum conditions are more common in males than in females, with a 2 or 3:1 male to female bias in prevalence consistently found in studies. Why this is the case is still not fully understood.

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

"But autism is clearly not 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."

Sex/gender differences in the brain

Researchers from the MIND Institute at University of California, Davis, USA, found sex differences in children with autism when looking at the organization of fibers in the corpus callosum, the largest bundle of nerve fibers in the brain.2

The study included 139 three-to-five year olds with autism (112 male/27 female) and 82 typically developing children (53 male/29 female). Using MRI, the researchers studied the pattern of nerve fibers projecting from the corpus callosum to different regions of the brain.

There were clear sex differences in the results. While both males and females with autism had alterations in regions of the corpus callosum connected to the frontal lobe, the pattern of alterations differed between the sexes.

In particular, males with autism had smaller callosal regions connecting to the orbitofrontal cortex, which is involved in emotional processing and reward-related decision-making. In contrast, females with autism had smaller callosal regions connecting to the anterior frontal cortex, which is involved in higher order 'executive function' such as planning.

The study suggests that males and females with autism should be evaluated separately and not assumed to share the same pattern of atypical brain structure. The study also suggests that differences in the corpus callosum are established early in development, before three years of age.

Genes and prenatal sex hormones

In another study, researchers from the George Washington University, USA, found sex differences in the levels of the gene 'RORA' in the brain. RORA regulates many genes linked to autism, including a gene that influences prenatal testosterone levels, a known risk factor for autism.

The team showed that RORA protein levels are higher in the brains of typically developing females compared to typically developing males, providing females with a buffer against RORA deficiency. RORA deficiency has previously been proposed as one factor that may make males more vulnerable to autism.

Female protective effect

Two papers in this new thematic series of the journal shed light on the 'female protective effect' -- the theory that there is a mechanism protecting the developing female brain from autism.

Researchers from University of California, Los Angeles, USA, investigated the risk of autism in males and females in over 1,000 families, and the rate at which autism re-occurred in siblings.

The results demonstrated the expected higher rates of autism in males compared to females, but also showed a significantly greater risk of autism for siblings of females with autism, compared to siblings of males with autism.

The researchers say this supports the 'female protective effect' hypothesis because females with autism carry greater genetic load predisposing them to develop the condition, compared to males. This could cause them to overcome the 'female protective effect', although this interpretation of their results awaits testing at the molecular level.

This greater genetic predisposition may run in families and means that siblings of females with autism are more likely to present autism.

A final study, led by University of California, San Francisco, Washington University in St Louis and Yale School of Medicine, USA, analyzed genetic data from over 4,500 families affected by autism. Their work found that no single gene is associated with the female protective effect. The authors conclude that the mechanism of this protection remains unknown, but that multiple genes could play a role.

Joseph Buxbaum, Co-editor in Chief of the journal Molecular Autism, said: "We are excited to be publishing such high quality, novel research on the important and previously neglected topic of the roles that sex and gender play in understanding autism."

Simon Baron-Cohen, Co-editor in Chief of the journal, added: "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.

"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."

Note: Material may have been edited for length and content. For further information, please contact the cited source.

BioMed Central


Meng-Chuan Lai, Simon Baron-Cohen, Joseph D. Buxbaum. Understanding autism in the light of sex/gender.   Molecular Autism, Published May 13 2015. doi: 10.1186/s13229-015-0021-4

Christine Wu Nordahl, Ana-Maria Iosif, Gregory S. Young, Lee Michael Perry, Robert Dougherty, Aaron Lee, Deana Li, Michael H. Buonocore, Tony Simon, Sally Rogers, Brian Wandell, David G Amaral. Sex differences in the corpus callosum in preschool-aged children with autism spectrum disorder.   Molecular Autism, Published May 13 2015. doi: 10.1186/s13229-015-0005-4

Valerie W. Hu, Tewarit Sarachana, Rachel M. Sherrard, Kristen M. Kocher. Investigation of sex differences in the expression of RORA and its transcriptional targets in the brain as a potential contributor to the sex bias in autism.   Molecular Autism, Published May 13 2015. doi: 10.1186/2040-2392-6-7

Donna M. Werling, Daniel H. Geschwind. Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins.   Molecular Autism, Published May 13 2015. doi: 10.1186/s13229-015-0004-5

Jake Gockley, A. Jeremy Willsey, Shan Dong, Joseph D. Dougherty, John N. Constantino, Stephan J. Sanders. The female protective effect in autism spectrum disorder is not mediated by a single genetic locus.   Molecular Autism, Published May 13 2015. doi: 10.1186/s13229-015-0014-3