Variants in Adjacent Oxytocin/Vasopressin Gene Region and Associations with ASD Diagnosis and Other Autism Related Endophenotypes

Abstract

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 endophenotypes were also noted: OXT rs6133010 was associated with IQ (full scale IQ, p = 0.008; nonverbal IQ, p = 0.010, verbal IQ, p = 0.006); and OXT rs4813625 and OXT rs877172 were associated with WB5HT levels (EA, p = 0.027 and p = 0.033, respectively). Additionally, we measured plasma OT (pOT) levels in a subsample (N = 54). Results show the three polymorphisms, OXT rs6084258, OXT rs11697250, and OXT rs877172, have significant association with pOT (EA, p = 0.011, p = 0.010, and p = 0.002, 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.

Genetics and epigenetics of autism: A Review

“…33 In addition, three polymorphisms of OXT (rs6084258, rs11697250, and rs877172) were found to associate with plasma oxytocin levels. 33 Using neuroimaging of 26 ASD children, a tentative association between the oxytocin receptor (OXTR) gene and N-acetylaspartate of the right medial temporal lobe in ASD has been reported 34 ; however, resequencing of the OXTR gene did not confirm any significant association with the three rare non-synonymous variations, that is, rs35062132 (R376G/C), rs151257822 (G334D), and g.8809426G>T (R150S), and ASD. 35 This is contradictory to a previous study that reported a significant association of these single nucleotide polymorphisms (SNP) with ASD and confirmation by functional studies.…”

“…Genetic variation in the OXT gene has found to be associated with phenotypic features of ASD that help to identify subgroups within the spectrum. A study of 108 European trios and another sample of 156 trios (207 probands) demonstrated a significant association between OXT rs6084258 and several endophenotypes of ASD . In addition, three polymorphisms of OXT (rs6084258, rs11697250, and rs877172) were found to associate with plasma oxytocin levels .…”

“…A study of 108 European trios and another sample of 156 trios (207 probands) demonstrated a significant association between OXT rs6084258 and several endophenotypes of ASD . In addition, three polymorphisms of OXT (rs6084258, rs11697250, and rs877172) were found to associate with plasma oxytocin levels . Using neuroimaging of 26 ASD children, a tentative association between the oxytocin receptor (OXTR) gene and N‐acetylaspartate of the right medial temporal lobe in ASD has been reported; however, resequencing of the OXTR gene did not confirm any significant association with the three rare non‐synonymous variations, that is, rs35062132 (R376G/C), rs151257822 (G334D), and g.8809426G>T (R150S), and ASD .…”

The Novel Ser18del AVP Variant Causes Inherited Neurohypophyseal Diabetes Insipidus by Mechanisms Shared with Other Signal Peptide Variants

“…Furthermore, she had isolated herself because of her physical symptoms. Although behavioural effects of AVP have been described [45], evidence that variants in the AVP gene causing FNDI should have any direct effect on behaviour is lacking. It has previously been reported using self-assessment tools that DI affects the quality of life [19].…”

Bridging the theory to evidence gap: a systematic review and analysis of individual × environment models of child development

“…found single nucleotide polymorphisms, such as the C allele of rs4813625, were associated with more internalizing behaviours in children (Francis et al 2016) and adult females (Love et al 2012).…”