Abstract
BackgroundArginine vasopressin has been shown to affect social and emotional behaviors, which is mediated by the arginine vasopressin receptor (AVPR1A). Genetic polymorphisms in the AVPR1A promoter region have been identified to be associated with susceptibility to social deficits in autism spectrum disorder (ASD). We hypothesize that alleles of polymorphisms in the promoter region of AVPR1A may differentially interact with certain transcriptional factors, which in turn affect quantitative traits, such as sociality, in children with autism.MethodsWe performed an association study between ASD and polymorphisms in the AVPR1A promoter region in the Korean population using a family-based association test (FBAT). We evaluated the correlation between genotypes and the quantitative traits that are related to sociality in children with autism. We also performed a promoter assay in T98G cells and evaluated the binding affinities of transcription factors to alleles of rs7294536.ResultsThe polymorphisms—RS1, RS3, rs7294536, and rs10877969—were analyzed. Under the dominant model, RS1–310, the shorter allele, was preferentially transmitted. The FBAT showed that the rs7294536 A allele was also preferentially transmitted in an additive and dominant model under the bi-allelic mode. When quantitative traits were used in the FBAT, rs7294536 and rs10877969 were statistically significant in all genotype models and modes. Luciferase and electrophoretic mobility-shift assays suggest that the rs7294536 A/G allele results in a Nf-κB binding site that exhibits differential binding affinities depending on the allele.ConclusionThese results demonstrate that polymorphisms in the AVPR1A promoter region might be involved in pathophysiology of ASD and in functional regulation of the expression of AVPR1A.
Highlights
Arginine vasopressin has been shown to affect social and emotional behaviors, which is mediated by the arginine vasopressin receptor (AVPR1A)
Genetic association study of the RS1 and RS3 microsatellite polymorphisms No associations were observed between RS3 and autism spectrum disorder (ASD) in the present replication sample set, though a significant association was observed in our previous analyses [23]
As the behavioral characteristics of the parents are not evaluated, there was limitation in examining relationship between Arginine vasopressin receptor 1A (AVPR1A) variants and behavioral functioning in the context of broader autism phenotype. In this family-based association study, we validated our previous study between ASD and the polymorphisms in AVPR1A with independent samples
Summary
Arginine vasopressin has been shown to affect social and emotional behaviors, which is mediated by the arginine vasopressin receptor (AVPR1A). Genetic polymorphisms in the AVPR1A promoter region have been identified to be associated with susceptibility to social deficits in autism spectrum disorder (ASD). One recent study reported association of RS1 and RS3 with repetitive behaviors, but not diagnosis of ASD [21] Both RS1 and RS3 showed differences in relative promoter activity as measured in the human neuroblastoma cell line, SH-SY5Y, with the shorter repeat alleles of RS1 and RS3 exhibiting decreased relative promoter activity [13]. Our previous studies have shown statistically significant associations between ASD and the shorter alleles of RS1 and RS3, which have been reported to be over-transmitted as risk alleles in other populations [23]. We have previously reported a statistically significant association of ASD with the single nucleotide polymorphisms (SNPs) rs10877969 and rs7294536 in the promoter region of AVPR1A [24]
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