Abstract
Sexual dimorphism in common disease is pervasive, including a dramatic male preponderance in autism spectrum disorders (ASDs). Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in females, sex-limited X-chromosome contribution, gene-environment interaction driven by differences in hormonal milieu, risk influenced by genes sex-differentially expressed in early brain development, or contribution from general mechanisms of sexual dimorphism shared with secondary sex characteristics. Utilizing a large single nucleotide polymorphism (SNP) dataset, we identify distinct sex-specific genome-wide significant loci. We investigate genetic hypotheses and find no evidence for increased genetic risk load in females, but evidence for sex heterogeneity on the X chromosome, and contribution of sex-heterogeneous SNPs for anthropometric traits to ASD risk. Thus, our results support pleiotropy between secondary sex characteristic determination and ASDs, providing a biological basis for sex differences in ASDs and implicating non brain-limited mechanisms.
Highlights
Autism spectrum disorders (ASDs) are characterized by deficits in use of language and social communication, sensory challenges, restricted interests, and repetitive behaviors that manifest in the first years of life
As ASDs are highly heritable, we examined evidence in single nucleotide polymorphism (SNP) data for five plausible genetic models that could generate sex bias
We identified distinct genomewide significant loci in each sex-specific dataset, and evaluated support in five analyses: 1) In contrast to rare variant contribution, we find no evidence for increased SNP genetic load in females
Summary
Autism spectrum disorders (ASDs) are characterized by deficits in use of language and social communication, sensory challenges, restricted interests, and repetitive behaviors that manifest in the first years of life. ASDs are estimated to occur in 1/42 boys and 1/189 girls, and are among the most heritable common disorders[1]. Estimates of heritability for idiopathic ASDs range between 38% and 90%, and autism-related traits in the general population are heritable[2,3,4,5,6,7,8,9]. An emerging body of evidence has identified a wide array of potential nongenetic risk factors[10,11]. The biological underpinnings and relevant environmental risk factors for ASDs are mostly unknown; the nearly five-fold difference in prevalence between males and females may provide critical clues. There is no definitive evidence regarding why males are more susceptible to ASDs [12]
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