Understanding Sex Differences in Autism

Friday, June 7, 2013 View Comments

Posted by Alycia Halladay, PhD, Autism Speaks senior director of environmental and clinical sciences

Over more than thirty years of autism research, one finding has stood out in its consistency: Boys are at least four times more likely than girls to be diagnosed with autism spectrum disorder (ASD).

But why?  What clues does this difference provide for understanding what causes autism? How should it guide how we develop behavioral therapies and other treatments?

In April, Autism Speaks organized a research symposium – “Sex Differences in Autism” – at the 2013 annual meeting of the Organization for the Study of Sex Differences (OSSD). OSSD seeks to enhance scientific understanding of gender differences in health conditions. At its meetings, it fosters collaboration among researchers and healthcare providers of diverse backgrounds.

Many health conditions differ in males and females. Often, one sex is more vulnerable or partially protected. By better understanding these differences, we hope to better understand and use such protective factors. Equally important is the need to develop the best therapies for each gender.

During the OSSD autism symposium, four researchers discussed their findings and ideas on sex difference in ASD: 

Peter Szatmari, M.D., of McMaster University, presented on “Re-thinking Sex Differences in Autism Spectrum Disorders.”

Aravinda Chakravarti, Ph.D., of Johns Hopkins University, discussed “Testing Genetic Etiologies of Sex Differences in Disease Incidence.”

Yale’s Stephan Sanders, M.D., presented “Evidence for Sex Bias Etiologies in Exome and Copy Number Variation (CNV) Data.

Janine LaSalle, Ph.D., of the University of California-Davis, discussed “Epigenetic Sex Differences from Environmental Exposures Relevant to Autism Spectrum Disorders.” (Read Dr. LaSalle’s blog on epigenetics, autism risk and pollution here.)

The discussion was lively and informative. In this blog post, I’d like to briefly summarize the latest thinking.

Our Leading Theories on Autism Gender Differences
1. Evidence is growing that females have a degree of protection against autism – versus just being less diagnosed. As recently reported on this website, researchers at Harvard Medical School found that, overall, it takes more autism risk genes to tip girls’ brain development onto the autism spectrum than it does for boys. Though the study looked only at inherited gene mutations, it may be that boys are also more vulnerable to nongenetic, or “environmental,” risk factors. (Read more about environmental factors and autism here.) 

2. The “female protect effect” may stem, in part, from our sex chromosomes. As you may remember from high-school biology, humans have 23 matched pairs of chromosomes. Sex is determined by the 23rd pair: Girls have two Xs. Boys have an X and Y. The extra protection for girls might come from those two matched Xs. They may provide a level of gene duplication that protects against a gene mutation on either X. By contrast, a mutation on a boy’s X or Y chromosome may prove more harmful because he lacks that matched backup copy.

3. From prenatal development through adulthood, males and females have very different levels of sex hormones such as testosterone and estrogen. We also know that these hormones play important roles in brain development. We need more research to investigate whether these different hormone levels can lower or increase risk.

4. In a broader sense, we know that many nongenetic factors – from prenatal nutrition to pollution exposure – can turn genes on or off at different times during development. Epigenetics is the term we use to describe these influences on gene activity. (See my blog, “What is epigenetics?” here.) We are only beginning to understand how epigenetics influences autism risk. However, we know there are male and female differences in epigenetic patterns. Again, we need more research to deepen our understanding.

What Does This Mean for Families?
What are the practical implications of this growing understanding? Certainly, by deepening our understanding of autism sex difference, we will better understand the genetic and environmental influences that contribute to the development of ASD.

Importantly gender differences suggest that girls and women may be more or less responsive to certain treatments than are boys and men. At this year’s International Meeting for Autism Research (IMFAR), for example, Emory University researchers described how boys and girls with autism use visual cues differently in social situations. (Read more here.)

Clearly we need more personalized treatments that take gender differences into account. And that means including more girls and women in autism treatment studies!

Also at IMFAR, a special interest group met to discuss the challenges and opportunities presented by behavioral, or “symptom,” differences in girls with ASD. In addition to researchers, this group included a young woman affected by autism as well as parents of affected girls. You can read more about this group here.   

Autism Speaks is currently funding several studies on gender differences and what they mean for understanding and treating autism. You can read more about them here. In closing, I’d like to thank the Autism Speaks community of families and other supporters for making this symposium and this research possible.