Novel rare variations of the oxytocin receptor (OXTR) gene in autism spectrum disorder individuals

Abstract

The oxytocin receptor (OXTR) gene has been implicated as a risk gene for autism spectrum disorder (ASD)-a neurodevelopmental disorder with essential features of impairments in social communication and reciprocal interaction. The genetic associations between common variations in OXTR and ASD have been reported in multiple ethnic populations. However, little is known about the distribution of rare variations within OXTR in ASD patients. In this study, we resequenced the full length of OXTR in 105 ASD individuals using an approach that combined the power of next-generation sequencing technology, long-range PCR and DNA pooling. We demonstrated that rare variants with minor allele frequency as low as 0.05% could be reliably detected by our method. We identified 28 novel variants including potential functional variants in the intron region and one rare missense variant (R150S). We subsequently performed Sanger sequencing and validated five novel variants located in previously suggested candidate regions in ASD individuals. Further sequencing of 312 healthy subjects showed that the burden of rare variants is significantly higher in ASDs compared with healthy individuals. Our results support that the rare variation in OXTR gene might be involved in ASD.Human Genome Variation (2015) 2, 15024; doi:10.1038/hgv.2015.24; published online 30 July 2015 INTRODUCTIONOxytocin is a nine-amino-acid peptide that acts as a hormone in peripheral tissues and as a neuromodulator in the brain. This short peptide was first noted and studied for its effects in promoting uterine contractions during childbirth and stimulating milk ejection, and is currently widely used for labor induction. Beyond these well-documented functions, recent studies demonstrate that oxytocin also has a critical role in regulating a wide range of social behaviors including pair bonding, maternal parenting and formation of social memory, 1 whereas the molecular mechanisms remain largely unknown. Oxytocin is synthesized in the hypothalamus, an almond-sized region deep inside the brain, and is released into the blood or diffused to other brain regions through exocytosis. Oxytocin exerts its effect by activating its specific receptor, the oxytocin receptor (OXTR)-a G-protein-coupled receptor-which relays the messages to downstream effectors.

Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment

“…Only one SNP overlapped with strong signatures of transcriptional function, a SNP occurring at nucleotide 213739 (NT213739, minor allele frequency: 0.32) (Figure 3b). The sequence containing NT213739 overlapped peaks of DNase hypersensitivity and CTCF binding within the large intron, a region proposed to contain cis -REs in humans (20, 61, 62). Based on this evidence we chose to further investigate the predictive power of NT213739 in two additional samples.…”

“…In the human OXTR third intron, the CTCF peak is found near a SNP, rs237887, that was predicted to be near a cis -RE, and associated with face recognition abilities (20) and ASD diagnosis (21). Additionally, the human intron may contain other cis -REs (61) and accumulates rare SNPs in cases of ASD (62). If the large intron of Oxtr contains cis -REs in multiple species, spatial organization of DNA by factors such as CTCF could offer a potentially general regulatory mechanism required for proper function of species or region-specific cis -REs.…”

Novel oxytocin receptor variants in laboring women requiring high doses of oxytocin

“…A variant in R150, R150S, was previously identified in an individual with autism spectrum disorder 24 . This residue is part of the oxytocin receptor ‘polar pocket’, which changes conformation during receptor activation and is involved in G-protein interaction 25–27 .…”

The potential role of oxytocin and perinatal factors in the pathogenesis of autism spectrum disorders – review of the literature

“…Genetic studies also suggested a role of OXT in ASD. The region of chromosome 3, in which OXTR is located is now considered a susceptibility locus, as it has repeatedly been found to be implicated in ASD (Liu et al, 2016;Jansen et al, 2006;Ebstein et al, 2009;Andari et al, 2010;Green et al, 2001;Guastella et al, 2010;Wang and Hatton, 2009;Sala et al, 2011;Schmidt et al, 2012;Guastella et al, 2008;Kurth et al, 2011). Wu et al have reported an association between two single nucleotide polymorphisms (SNP) in the OXTR related to the occurrence of ASD (Wu et al, 2005).…”