Investigation of Parent-of-Origin Effects in Autism Spectrum Disorders
The detection of Parent-of-Origin (PofO) effects aims to identify whether or not the functionality of alleles, and in turn associated phenotypic traits, depends on the parental origin of the alleles. Autism Spectrum Disorders (ASD) are considered to be heritable neurodevelopmental disorders but in the majority of ASD cases, the genetic cause cannot be identified. Exploring and identifying possible PofO effects is an important step in trying to understand the genetic mechanisms underlying ASDs.
To investigate parent-of-origin effects, such as imprinting and maternal genetic effects, in ASD using Genome Wide Association Study (GWAS) datasets.
We use a multinomial model run in the software EMIM to investigate parent-of-origin effects in the Autism Genomic Project (AGP) dataset. Since this model is complex, it has less power than a typical GWAS analysis, and given that the GWA threshold of 5x10-8 has been considered strict, we employ a Bayesian adapted threshold that takes into account the power at each SNP.
Based on the use of the Bayesian threshold approach, we found 103 different regions that were found to have an imprinting and/or maternal genetic effect(s). We found two results < 5 x10-7, one for paternal imprinting on chromosome 7 and the other for a maternal genetic effect on chromosome 15 in the MGA gene. We found 4 regions that have been previously identified as showing evidence of PofO effects in ASD. These include a maternal genetic effect in a region that was also identified as having a maternal genetic effect by Tsang et al. 2013 on chromosome 11 in the MAML2 gene and a maternal imprinting effect on chromosome 18 where Yuan and Dougherty 2014 found a maternal genetic effect (it is worth noting that maternal imprinting and maternal genetic effects have been known to mimic each other).
To our knowledge, this is the first genome-wide study to test for both imprinting and maternal genetic effects simultaneously in ASD and the first to implement the Bayesian adapted thresholds that take into consideration the power of the test. We found some promising results that we are currently hoping to replicate in the Simons Simplex Collection autism data set.