A genome-wide investigation into parent-of-origin effects in autism spectrum disorder identifies previously associated genes including SHANK3

Abstract

Autism spectrum disorder (ASD) is known to be a heritable neurodevelopmental disorder affecting more than 1% of the population but in the majority of ASD cases, the genetic cause has not been identified. Parent-of-origin effects have been highlighted as an important mechanism in the pathology of neurodevelopmental disorders such as Prader-Willi and Angelman syndrome, with individuals with these syndromes often exhibiting ASD symptoms. Consequently, systematic investigation of these effects in ASD is clearly an important line of investigation in elucidating the underlying genetic mechanisms. Using estimation of maternal, imprinting and interaction effects using multinomial modelling (EMIM), we simultaneously investigated imprinting, maternal genetic effects and associations in the Autism Genome Project and Simons Simplex Consortium genome-wide association data sets. To avoid using the overly stringent genome-wide association study significance level, we used a Bayesian threshold that takes into account the sample size, allele frequency and any available prior knowledge. Between the two data sets, we identified a total of 18 imprinting effects and 68 maternal genetic effects that met this Bayesian threshold criteria, but none met the threshold in both data sets. We identified imprinting and maternal genetic effects for regions that have previously shown evidence for parent-of-origin effects in ASD. Together with these findings, we have identified maternal genetic effects not previously identified in ASD at a locus in SHANK3 on chromosome 22 and a locus in WBSCR17 on chromosome 7 (associated with Williams syndrome). Both genes have previously been associated with ASD.