Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Nov 16:7:58.
doi: 10.1186/s13293-016-0112-8. eCollection 2016.

The role of sex-differential biology in risk for autism spectrum disorder

Donna M Werling  1
Affiliations
Review

The role of sex-differential biology in risk for autism spectrum disorder

Donna M Werling. Biol Sex Differ. .

Abstract

Autism spectrum disorder (ASD) is a developmental condition that affects approximately four times as many males as females, a strong sex bias that has not yet been fully explained. Understanding the causes of this biased prevalence may highlight novel avenues for treatment development that could benefit patients with diverse genetic backgrounds, and the expertise of sex differences researchers will be invaluable in this endeavor. In this review, I aim to assess current evidence pertaining to the sex difference in ASD prevalence and to identify outstanding questions and remaining gaps in our understanding of how males come to be more frequently affected and/or diagnosed with ASD. Though males consistently outnumber females in ASD prevalence studies, prevalence estimates generated using different approaches report male/female ratios of variable magnitude that suggest that ascertainment or diagnostic biases may contribute to the male skew in ASD. Here, I present the different methods applied and implications of their findings. Additionally, even as prevalence estimations challenge the degree of male bias in ASD, support is growing for the long-proposed female protective effect model of ASD risk, and I review the relevant results from recurrence rate, quantitative trait, and genetic analyses. Lastly, I describe work investigating several sex-differential biological factors and pathways that may be responsible for females' protection and/or males' increased risk predicted by the female protective effect model, including sex steroid hormone exposure and regulation and sex-differential activity of certain neural cell types. However, much future work from both the ASD and sex differences research communities will be required to flesh out our understanding of how these factors act to influence the developing brain and modulate ASD risk.

Keywords: Autism; Autism spectrum disorder; Female protective effect; Prevalence; Sex differences; Testosterone.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Approaches used to estimate ASD prevalence and male:female ratio. Different approaches may identify different overall, and sex-specific, prevalence rates. a Screening populations in full, irrespective of existing diagnostic status. b Analysis of records in existing, standardized registries. c Collating and/or sampling and interpreting available records from scholastic or medical records. d Baby siblings studies, where researchers prospectively monitor the younger siblings of autistic children for recurrence of ASD and other traits of interest. Filled figures represent individuals with ASD
Fig. 2
Fig. 2
Sex-differential ASD risk can be represented by a multiple-threshold liability/FPE model. a Under a multiple threshold liability/female-protective effect (FPE) model, risk or liability for ASD is quantitative and distributed in the population, and males and females have different minimum liability thresholds that are sufficient to lead to an ASD diagnosis. The tail of the distribution filled in gray indicates those individuals in the population with diagnosed ASD. b A closer look at the region marked with a green, dotted box in a. A key prediction from the FPE model is that among diagnosed individuals, females will have greater ASD liability than males. A secondary prediction is that non-diagnosed females may carry, or be exposed to, relatively high ASD liability but they do not present symptoms that meet criteria for diagnosis; mothers of autistic children may include such females. c Examples of sex-differential biological factors proposed to contribute to males’ and females’ shifted liability thresholds and differential risk for ASD. Figure adapted from Werling and Geschwind [46]
Fig. 3
Fig. 3
Microglia and/or astrocytes may have a role in ASD pathophysiology and sex-differential biology. ASD risk genes, when disrupted, affect processes in the developing brain such as molecular pathways, cellular functions, and neural circuits (thick green arrows), which subsequently lead to an ASD phenotype. Sex-differential regulatory mechanisms also influence different, and possibly overlapping, processes (thick purple arrows). A gene recent gene expression analysis by Werling and colleagues (2016) demonstrated that genes associated with the functions of microglia and/or astrocytes show higher expression in males (versus females) as well as higher expression in the ASD brain (versus controls), suggesting that these cell types may contribute to both typical sex differences in the brain and ASD pathophysiology. This is one potential pathway that may contribute to ASD’s male-biased prevalence
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Diagnostic Stat Man Ment Disord 5th Ed. Arlington, Virginia: American Psychiatric Association; 2013.
    1. Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res. 2009;65:591–8. doi: 10.1203/PDR.0b013e31819e7203. - DOI - PubMed
    1. Elsabbagh M, Divan G, Koh YJ, Kim YS, Kauchali S, Marcín C, Montiel-Nava C, Patel V, Paula CS, Wang C, Yasamy MT, Fombonne E. Global prevalence of autism and other pervasive developmental disorders. Autism Res. 2012;5:160–79. doi: 10.1002/aur.239. - DOI - PMC - PubMed
    1. Lai MC, Lombardo MV, Auyeung B, Chakrabarti B, Baron-Cohen S. Sex/gender differences and autism: setting the scene for future research. J Am Acad Child Adolesc Psychiatry. 2015;54:11–24. doi: 10.1016/j.jaac.2014.10.003. - DOI - PMC - PubMed
    1. Halladay AK, Bishop S, Constantino JN, Daniels AM, Koenig K, Palmer K, Messinger D, Pelphrey K, Sanders SJ, Singer AT, Taylor JL, Szatmari P. Sex and gender differences in autism spectrum disorder: summarizing evidence gaps and identifying emerging areas of priority. Mol Autism. 2015;6:36. doi: 10.1186/s13229-015-0019-y. - DOI - PMC - PubMed

LinkOut - more resources