Analysis of Sex and Recurrence Ratios in Simplex and Multiplex Autism Spectrum Disorder Implicates Sex-Specific Alleles as Inheritance Mechanism

Abstract

Autism spectrum disorder (ASD) has a strong male bias, with four times as many affected males as females. ASD is hypothesized to follow a polygenic disease model. While prior literature has linked several genes with the disorder, the specific genetic causes and inheritance methods underlying the condition are still widely unknown. Here, we investigate two popular theories of polygenic inheritance that could account for the male preponderance of ASD: a multiple-threshold model in which females must have a higher genetic burden in order to be affected, and a sex-specific allele model in which variants in genes and regulatory regions have sex-specific effects. We use phenotypic information from the Simons Simplex Collection of families with simplex ASD and the iHART collection of families with multiplex ASD to compare ratios of affected males and females and sex-specific recurrence rates with predictions from each of the inheritance mechanisms. Our results suggest that a sex-specific allele model can be used to explain the male bias behind ASD inheritance.