Variants in adjacent oxytocin/vasopressin gene region and associations with ASD diagnosis and autism related endophenotypes

Background: There has been increasing interest in oxytocin (peptide: OT, gene: OXT) as a treatment pathway for neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Neurodevelopmental disorders affect functional, social, and intellectual abilities. With advances in molecular biology, research has connected multiple gene regions to the clinical presentation of ASD. Studies have also shown that the neuropeptide hormones OT and arginine vasopressin (AVP) influence mammalian social and territorial behaviors and may have treatment potential for neurodevelopmental disorders. Published data examining molecular and phenotypic variation in ASD, such as cognitive abilities, are limited. Since most studies have focused on the receptors in the OT-AVP system, we investigated genetic variation within peptide genes for association with phenotypic ASD features that help identify subgroups within the spectrum.
Methods: In this study, TDT analysis was carried out utilizing FBAT in 207 probands (156 trios) and a European Ancestry (EA) subsample (108 trios). The evolutionarily related and adjacent genes of OXT and AVP were studied for associations between the tagged single nucleotide polymorphisms and ASD diagnosis, social abilities, restrictive and repetitive behaviors, and IQ for cognitive abilities. Additionally, relationships with whole blood serotonin (WB5HT) were explored because of the developmental relationships connecting plasma levels of OT and WB5HT within ASD.
Results: Results indicate significant association between OXT rs6084258 (p=0.001) and ASD. Associations with several intermediate phenotypes were also noted: OXT rs6133010 was associated with IQ (full scale IQ, p=0.008; nonverbal IQ, p=0.009, verbal IQ, p=0.006); and OXT rs6084258 and OXT rs877172 were associated with WB5HT levels (EA, p=0.029 and p=0.050, respectively). Additionally, we measured plasma OT (pOT) levels in a subsample (N=54). Results show the same two polymorphisms, OXT rs877172 and OXT rs6084258, have significant association with pOT (EA, p=0.002 and p=0.011, respectively).
Conclusions: These findings suggest that SNPs near OXT and AVP are associated with diagnosis of ASD, social behaviors, restricted and repetitive behaviors, IQ, pOT, and WB5HT. Future studies need to replicate these findings and examine gene-interactions in other neurodevelopmental disorders. Mechanisms of action may influence early social and cognitive development that may or may not be limited to ASD diagnosis.

背景：催产素（肽：OT，基因：OXT）作为神经发育障碍（如孤独症谱系障碍，Autism Spectrum Disorder, ASD）的治疗途径，正受到越来越多的关注。神经发育障碍影响个体的功能、社交及智力能力。随着分子生物学的进展，研究已将多个基因区域与ASD的临床表型关联起来。研究还表明，神经肽激素OT和精氨酸加压素（arginine vasopressin, AVP）可影响哺乳动物的社交与领地行为，并可能对神经发育障碍具有治疗潜力。目前，探究ASD分子与表型（如认知能力）变异的已发表数据较为有限。由于多数研究聚焦于OT-AVP系统中的受体，本研究则探究了肽基因内的遗传变异与ASD表型特征的关联——这些特征有助于识别谱系内的亚群。
方法：本研究采用FBAT工具对207例先证者（156个家系 trio）及欧洲血统（European Ancestry, EA）亚样本（108个家系）进行传递不平衡检验（Transmission Disequilibrium Test, TDT）分析。针对OXT与AVP的进化相关及相邻基因，探究了标签单核苷酸多态性（tagged single nucleotide polymorphism, SNP）与ASD诊断、社交能力、限制性重复行为及认知能力（以IQ衡量）之间的关联。此外，鉴于ASD患者中OT血浆水平与全血5-羟色胺（whole blood serotonin, WB5HT）存在发育相关性，本研究还探究了上述基因变异与WB5HT的关联。
结果：OXT基因rs6084258位点（p=0.001）与ASD存在显著关联。同时观察到与若干中间表型的关联：OXT基因rs6133010位点与IQ相关（全量表IQ，p=0.008；非言语IQ，p=0.009；言语IQ，p=0.006）；OXT基因rs6084258与rs877172位点与EA亚样本的WB5HT水平相关（p值分别为0.029和0.050）。此外，本研究在一个亚样本（N=54）中检测了血浆催产素（plasma oxytocin, pOT）水平，结果显示上述两个多态性位点（OXT rs877172与rs6084258）与EA亚样本的pOT水平显著相关（p值分别为0.002和0.011）。
结论：本研究结果表明，OXT与AVP基因附近的单核苷酸多态性（SNP）与ASD诊断、社交行为、限制性重复行为、IQ、pOT及WB5HT相关。未来研究需重复验证这些发现，并探究其他神经发育障碍中的基因互作。其作用机制可能影响早期社交与认知发育，且这种影响可能不限于ASD诊断范畴。