Autism’s skewed gender ratio explained

The skewed gender ratio in autism spectrum disorder (ASD) may be explained by differences in heritability in males and females, an international study has found.

“ASD is a neurodevelopmental disorder that is more prevalent in males than in females. The cause of ASD is largely genetic, but the association of genetics with the skewed gender ratio is not yet understood,” wrote the researchers from the Chinese University of Hong Kong (CUHK), Icahn School of Medicine at Mount Sinai in the US, Karolinska Institutet in Sweden, and other institutions. “To our knowledge, no large population-based study has provided estimates of heritability by gender.”

To estimate the sex-specific heritability of ASD, the researchers conducted a population-based retrospective analysis (n=1,047,619; male, 51.38 percent) using national health registers of non-twin siblings and cousins born between 1 January 1985 and 31 December 1998 in Sweden, with follow-up to 19 years of age. Data analysis was performed from August 2022 to November 2023. [JAMA Psychiatry 2024;doi:10.1001/jamapsychiatry.2024.0525]

A total of 12,226 individuals (1.17 percent), including 8,128 males (1.51 percent) and 4,098 females (0.80 percent), were diagnosed with ASD by the age of 19 years. “ASD heritability was estimated at 87.0 percent for males and 75.7 percent for females, with an estimated difference of 11.3 percent [95 percent confidence interval, 1.0-21.6],” reported the researchers.

Estimates were adjusted for differences in prevalence by sex, birth year, and maternal and paternal age. “Compared with previous studies, we used newly developed statistical estimation techniques, allowing for detailed inclusion of fixed parameters and providing better adjustments,” noted the researchers. [JAMA Psychiatry 2019;76:1035-1043; JAMA 2017;318:1182-1184; JAMA Psychiatry 2024;doi:10.1001/jamapsychiatry.2024.0525]

In agreement with previous studies, the shared environmental effects were close to zero and lacked statistical significance in all models, indicating there was no support for shared environmental contributions.

“Our study indicates that heritability may play a more significant role in males than females,” stated Professor Benjamin Hon-Kei Yip of the Jockey Club School of Public Health and Primary Care, CUHK. “It is also possible that females are less impacted by additive genetic sources or are particularly vulnerable to other risk sources, such as classical environmental factors found in the built environment, differences in the cultural environment leading to ascertainment or diagnosis differences, genetic sources not inherited additively [eg, de novo variants], or deficits in the model or its assumptions.”

The results underscore the importance of taking gender differences into account in ASD research and treatment. This may pave the way for future studies focusing on rare mutations in female patients or personalized treatment approaches for ASD based on patients’ unique genetic profiles.

“The study is a crucial step forward in unravelling the complexities of ASD. It not only provides clarity on the genetic predisposition of the condition, but also sets a new direction for global research to include sex-specific analysis,” commented Professor Sven Sandin of the Department of Psychiatry, Icahn School of Medicine, Mount Sinai, US. “The potential impact for future research is profound, as the findings could lead to breakthroughs in understanding the nuanced genetic landscape of ASD and its associated conditions.”