Modeling rare coding variation on chromosome X provides insight into the genetics and differential sex prevalence of autism spectrum disorder

Autism spectrum disorder (ASD) is estimated to be up to four times as common in males as in females, yet the causes of this prevalence difference are not well established. One possible driver is genetic variation on the X chromosome, as it contains genes capable of contributing to ASD (e.g., PTCHD1, MECP2) and is known to play a role in genetic disorders with differential sex prevalence (e.g., color blindness). However, a lack of power compared to the autosomes combined with the complexities of modeling its biology have led to the X being largely overlooked in sequencing studies. Here, we develop quantitative X-linked TADA, a new model designed specifically for application to this chromosome, and use it to analyze rare variation from 50,663 individuals with ASD (and 136,670 individuals total). We find 9 genes on the X associated with ASD at a false discovery rate (FDR) < 0.05 and an additional 9 genes at FDR < 0.2, with many of these previously identified as involved in specific neurodevelopmental disorders. Point estimates of the liability conferred by de novo variants on the X are similar in females and males, with both sexes estimates elevated >20% above the corresponding autosomal values. We also develop a general theory of how X-linked variation of any additive or non-additive effect influences liability and describe its implications for prevalence. Using this theory and our empirical results, we show how genetic variation on the X could contribute to the sex-differential prevalence of ASD.