Genomic and epigenetic evidence for oxytocin receptor deficiency in autism

Abstract

Background: Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders.

Oxytocin pathways in the intergenerational transmission of maternal early life stress

“…Hypermethylation of the OXTR promoter including a CpG rich region (CpG island spanning from −2860 to +1342 bases relative to the transcription start site) reduced OTR mRNA expression by approximately 70%. Methylation-induced downregulation of the OTR was also confirmed in post mortem cortical brain tissue of male patients with autism spectrum disorders (Gregory et al, 2009). Two recent studies revealed a role for OXTR DNA methylation in peripheral blood cells to predict risk for PPD (Bell et al, 2015; Kimmel et al, 2016).…”

“…In addition to sequence variations in OT pathway genes, epigenetic modifications of the OXTR gene have recently attracted considerable attention in clinical, behavioral, and cognitive neurosciences (Kumsta et al, 2013) and have been associated with different phenotypes including maternal PPD (Bell et al, 2015; Kimmel et al, 2016), amygdala reactivity (Puglia et al, 2015), autism (Gregory et al, 2009), and social anxiety disorder (Ziegler et al, 2015) amongst others. Briefly, epigenetics encompasses a set of biochemical modifications of genome function (e.g., histone modifications, DNA methylation, or the effects of small non-coding RNAs, e.g., micro RNAs) that interfere with transcriptional or translational events and can therefore regulate gene expression.…”

“…GG homozygous (rs53576) women, who were not depressed during pregnancy had an almost 3-fold risk ( adjusted OR: 2.63 ) to develop PPD for every 10% increase of DNA methylation at a CpG dinucleotide located on intron 1, 934 basepairs upstream of the translation start site (CpG −934) compared to A allele carriers. Hypermethylation of this specific CpG has been shown to be associated with reduced OTR expression in the cortex of deceased autism patients (Gregory et al, 2009), suggesting that hypermethylation measured in peripheral tissue of this specific CpG may partly reflect OTR expression regulation in brain tissue (Bell et al, 2015). In contrast, another study found lower OXTR DNA methylation in an intronic region (cg 12695586) in women with high depressive symptoms both pre- and postpartum compared to women with PPD symptoms only (Kimmel et al, 2016).…”

“…However, comparability between studies is difficult because they differ greatly in target sequences and partly show effects that are not in the expected direction. Moreover, with one exception (Gregory et al, 2009), these studies did not quantify OTR mRNA expression levels varying as a function of methylation status; thus the biological significance of the observed methylation changes is not addressed. Another important limitation of this body of literature is that it has exclusively focused on DNA methylation of the OXTR gene.…”

A Candidate Circuit Approach to Investigating Autism

“…As regards this latter pathway, decreased circulating oxytocin levels in individuals with ASD has been observed (Modahl et al, 1998), and administration of oxytocin to individuals with ASD has been reported to reduce repetitive behaviors (Hollander et al, 2003), enhance retention of social cognition (Hollander et al, 2007) and improve emotional recognition (Guastella et al, 2010). Furthermore, OXTR, which is located at chromosome 3p25 and encodes a G-protein coupled receptor, has been associated with ASD in numerous studies (Wu et al, 2005;Ylisaukko-oja et al, 2006;Jacob et al, 2007;Lerer et al, 2008;Yrigollen et al, 2008;Gregory et al, 2009;Liu et al, 2010;Wermter et al, 2010).…”