Sex/gender differences and autism: setting the scene for future research

Abstract

Objective: The relationship between sex/gender differences and autism has attracted a variety of research ranging from clinical and neurobiological to etiological, stimulated by the male bias in autism prevalence. Findings are complex and do not always relate to each other in a straightforward manner. Distinct but interlinked questions on the relationship between sex/gender differences and autism remain underaddressed. To better understand the implications from existing research and to help design future studies, we propose a 4-level conceptual framework to clarify the embedded themes.

Method: We searched PubMed for publications before September 2014 using search terms "'sex OR gender OR females' AND autism." A total of 1,906 articles were screened for relevance, along with publications identified via additional literature reviews, resulting in 329 articles that were reviewed.

Results: Level 1, "Nosological and diagnostic challenges," concerns the question, "How should autism be defined and diagnosed in males and females?" Level 2, "Sex/gender-independent and sex/gender-dependent characteristics," addresses the question, "What are the similarities and differences between males and females with autism?" Level 3, "General models of etiology: liability and threshold," asks the question, "How is the liability for developing autism linked to sex/gender?" Level 4, "Specific etiological-developmental mechanisms," focuses on the question, "What etiological-developmental mechanisms of autism are implicated by sex/gender and/or sexual/gender differentiation?"

Conclusions: Using this conceptual framework, findings can be more clearly summarized, and the implications of the links between findings from different levels can become clearer. Based on this 4-level framework, we suggest future research directions, methodology, and specific topics in sex/gender differences and autism.

Keywords: autism; etiology; gender; nosology; sex.

Figure 1

The 4-level framework. Note: This conceptual framework comprises 4 levels of research themes (in bold) and main research questions (in italics). They are distinct but interlinked and mutually informative. Level 1 affects the discovery and interpretation of findings at all other levels (black arrows). Level 2 findings can contribute to the formulation, testing, and revision of etiological models and mechanisms (gray arrows). General etiological models from level 3 can enlighten investigation into specific mechanisms at level 4 (striped arrow). Finally, all findings from levels 2 to 4 can feed back to level 1 reflection (white arrows) for the process of epistemic iteration.

Figure 2

Multi-factorial multi-threshold versus sex/gender-differential liability models. Note: (A) In the original multi-threshold model, genetic liability for autism is normally distributed in the population, and the minimum genetic liability sufficient to cause autism (threshold) is greater in females than in males. (B) In the revised sex/gender-differential liability model, female-specific factors shift females’ total liability distribution (including genetic, environmental, and other factors) away from—and male-specific factors shift males’ distribution toward—a single threshold. ASD = autism spectrum disorder; X chr = X chromosome; Y chr = Y chromosome.