Autism Spectrum Disorder (ASD) cases are predominantly male, with a male-to-female ratio of about 4 to 1. However, medical academia has been unable to determine the cause of this gender difference. A recent international study co-led by The Chinese University of Hong Kong (CUHK)’s Faculty of Medicine (CU Medicine) and its partners in Europe and the U.S. has made a significant breakthrough in understanding the skewed sex ratio observed in ASD. The study revealed that the condition’s heritability is higher in males than females by 11 percentage points, meaning that males are more vulnerable to genetic variance related to ASD. Study details have been published in the renowned international journal JAMA Psychiatry.
A breakthrough in the understanding of ASD
ASD is a neurodevelopmental condition that includes difficulties with communication, social interaction and adjustment to unexpected changes. It is known that this condition is explained more by multigene effects (i.e. additive genetics) than by rare mutations with large effects. Male patients are more likely to be diagnosed compared to females. However, it is unclear why the sex ratio is skewed.
For the current study, a population-based analysis was undertaken by an international research team consisting of researchers from CU Medicine, Icahn School of Medicine at Mount Sinai in the U.S., Karolinska Institutet in Sweden and other institutions. They leveraged the anonymised data of the national health registers of non-twin siblings and cousins from Sweden. The participants, born between 1985 and 1998, were followed up to the age of 19. The data analysis, which took place from August 2022 to November 2023, included 1,047,649 individuals across 456,832 families.
Researchers employed sophisticated statistical models to estimate the relative variance in ASD risk attributable to sex-specific additive genetics, shared environmental effects and a common residual term. This residual term conceptually captured other factors promoting individual behavioural variation, including maternal effects (such as preterm birth), rare genetic variants or gene-environment interactions. The estimates were carefully adjusted for differences in prevalence due to birth year and maternal and paternal age.
Paving the way for personalised care strategies for individuals with ASD
Out of the entire cohort, 12,226 cases (1.17%) received an ASD diagnosis, with a higher prevalence in males (1.51%) than females (0.80%). The heritability of ASD was estimated at 87% for males and 75.7% for females, a difference of approximately 11 percentage points between the sexes. This shows that genetic factors play a more substantial role in the aetiology of male ASD cases, while residual factors have higher influence on female cases. Notably, the study found no evidence of shared environmental contributions to ASD.
Professor Benjamin Yip Hon-kei, the corresponding author of the research paper and Associate Professor at CU Medicine’s The Jockey Club School of Public Health and Primary Care, stated, “These findings indicate that genetic variability may play a more significant role in males with ASD than females. Our study underscores the importance of considering sex differences in ASD research and treatment, potentially leading to future studies which target the rare mutations in female patients. Therefore, more personalised approaches may be developed to support individuals with ASD, considering their unique genetic makeup.”
This research collaboration between CU Medicine and its partners in Europe and the U.S. is a testament to the importance of collaborative, cross-disciplinary efforts in advancing the understanding of neurodevelopmental disorders.
Another corresponding author of the research paper, Professor Sven Sandin, Associate Professor from the Department of Psychiatry of the Icahn School of Medicine at Mount Sinai and also an Applied Biostatistician from the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet, concluded, “This 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. The implications for future studies are profound, as this research could lead to breakthroughs in understanding the nuanced genetic landscape of ASD and other related conditions.”
For more details
Faculty of Medicine, CUHK: https://bit.ly/3wtBvVa
Full article of the study: https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2817601
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