Replicative genetic association study between functional polymorphisms in AVPR1A and social behavior scales of autism spectrum disorder in the Korean population

Abbreviations ADI-A1: Failure to use nonverbal behaviors to regulate social interaction; ADIA2: Failure to develop peer relationship; ADI-A3: Lack of shared enjoyment; ADI-A4: Lack of socioemotional reciprocity; ANOVA: Analysis of variance; ASD: Autism spectrum disorder; ASDS: Asperger Syndrome Diagnostic Scale; AVP: Arginine vasopressin; AVPR1A: Arginine vasopressin receptor 1A; Df: Degree of freedom; EMSA: Electrophoretic mobility-shift assay; FBAT: Family-based association test; HBAT: Haplotype family-based association test; IRB: Institutional Review Board; K-ADI-R: Korean version of the Autism Diagnostic Interview-Revised; K-ADOS: Korean version of the Autism Diagnostic Observation Schedule; K-CBCL: Korean Child Behavior Checklist; KEDI-WISC-R: Korean Educational Development Institute-Wechsler Intelligence Scale for Children-Revised; K-SMS: Korean version of the Social Maturity Scale; MAF: Minor allele frequency; PDD-NOS: Pervasive developmental disorder that were not otherwise specified; RLUs: Relative luciferase units; SCQ: Social Communication Questionnaires; SNPs: Single nucleotide polymorphisms; SRS: Social Responsiveness Scale; TDT: Transmission disequilibrium test; VABS: Vineland Adaptive BehaviorAbstract Background 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). 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. Methods We 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. Results The 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. Conclusion These 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.This work has been supported by the Healthcare Technology R&D project (no. HI12C0021) by the Ministry of Health and Welfare, Republic of Korea; the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2014R1A2A1A110 53289 and NRF-2017M3C7A1027467