Abstract
BackgroundA 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD). Epidemiological and genetic studies suggest a female protective effect (FPE) may account for part of this bias; however, the mechanism of such protection is unknown. Quantitative assessment of ASD symptoms using the Social Responsiveness Scale (SRS) shows a bimodal distribution unique to females in multiplex families. This leads to the hypothesis that a single, common genetic locus on chromosome X might mediate the FPE and produce the ASD sex bias. Such a locus would represent a major therapeutic target and is likely to have been missed by conventional genome-wide association study (GWAS) analysis.MethodsTo explore this possibility, we performed an association study in affected versus unaffected females, considering three tiers of single nucleotide polymorphisms (SNPs) as follows: 1) regions of chromosome X that escape X-inactivation, 2) all of chromosome X, and 3) genome-wide.ResultsNo evidence of a SNP meeting the criteria for a single FPE locus was observed, despite the analysis being well powered to detect this effect.ConclusionsThe results do not support the hypothesis that the FPE is mediated by a single genetic locus; however, this does not exclude the possibility of multiple genetic loci playing a role in the FPE.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-015-0014-3) contains supplementary material, which is available to authorized users.
Highlights
A 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD)
Targeted association study: tier 1 single nucleotide polymorphism (SNP) To test the hypothesis that the female protective effect (FPE) is mediated by a common variant at a single locus, we performed an association test comparing 208 affected females against 151 unrelated unaffected females
Since the FPE is unique to females, we reasoned that the region of the genome that has the greatest potential for sexual dimorphism would be the most likely location for such a locus, and the first tier of our analysis was performed on 451 SNPs that are unique to chromosome X and that escape X-inactivation (Figure 3 and Additional file 3: Table S4)
Summary
A 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD). Quantitative assessment of ASD symptoms using the Social Responsiveness Scale (SRS) shows a bimodal distribution unique to females in multiplex families. This leads to the hypothesis that a single, common genetic locus on chromosome X might mediate the FPE and produce the ASD sex bias. Such a locus would represent a major therapeutic target and is likely to have been missed by conventional genome-wide association study (GWAS) analysis. One approach is to try to identify a subset of females in whom the FPE is absent, for example, females with ASD
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