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. INTRODUCTIONAutism spectrum disorder (ASD) is a complex and heterogeneous neurodevelopmental disorder characterised by patterns of repetitive behaviours and deficits in language and social behaviour. ASD is known to be heritable, with earlier heritability estimates ranging from 0.85 to 0.92 1 to a more current heritability estimate of 0.524, 2 with most of this believed to be due to common rather than rare variation. 2 Gaugler et al 2 also estimated that 41% of the risk for ASD is due to environmental factors, which include prenatal, perinatal and postnatal environmental factors. Several genome-wide association studies (GWASs) have been performed on common variants in ASD using family studies, but the most significant results from these studies show modest effect size 3-5 and therefore, have low power to replicate. 4 Despite growing evidence from investigations of rare and de novo structural and sequence variation in ASD, 6 the aetiology of the majority of ASD cases remains unexplained, suggesting that there are complex genetic mechanisms underlying the disorder. There is also evidence to suggest that there is a complex relationship between these underlying genetic factors and environmental factors. 7 Broadly speaking, parent-of-origin effects consist of genetic effects on the phenotype of an offspring that are dependent on the parental origin of the...

On the accuracy in high‐dimensional linear models and its application to genomic selection

“…In contrast to LA, GWAS are based on unrelated individuals, and as a result, larger sample sizes can be considered. GWAS enabled the discovery of many single‐nucleotide polymorphism (SNP)–trait associations in humans (e.g., age‐related macular degeneration in Fritsche et al, and autism spectrum disorder in Connolly, Anney, Gallagher, & Heron, ).…”

Genomic Imprinting As a Window into Human Language Evolution

“…Of particular interest for language is the LRRC16A gene, in which risk variants are maternally overtransmitted in cases of ASD . It has been suggested that this gene may be associated with language deficits, although in the original study it did not reach statistical significance …”

“…Furthermore, autism spectrum disorder (ASD) and schizophrenia both have communication‐related phenotypes . Both have previously been linked to imprinting and more recent empirical work strengthens this association . Of particular interest for language is the LRRC16A gene, in which risk variants are maternally overtransmitted in cases of ASD .…”

“…[86,87] Both have previously been linked to imprinting [88] and more recent empirical work strengthens this association. [89,90] Of particular interest for language is the LRRC16A gene, in which risk variants are maternally overtransmitted in cases of ASD. [89] It has been suggested that this gene may be associated with language deficits, [89] although in the original study it did not reach statistical significance.…”

“…[89,90] Of particular interest for language is the LRRC16A gene, in which risk variants are maternally overtransmitted in cases of ASD. [89] It has been suggested that this gene may be associated with language deficits, [89] although in the original study it did not reach statistical significance. [74] One point that emerges from the investigation of the genes that are known to underpin language is that it is likely that any gene affecting language also has some degree of pleiotropy with other behavioral or morphological phenotypes.…”