Evidence for Association Between OXTR Gene and ASD
Clinical Phenotypes
Lucas de Oliveira Pereira Ribeiro
1
&
Pedro Vargas-Pinilla
2
&
Djenifer B. Kappel
2
&
Danae Longo
2
&
Josiane Ranzan
3
&
Michele Michelin Becker
3
&
Rudimar dos Santos Riesgo
3
&
Lavinia Schuler-Faccini
2
&
Tatiana Roman
2
&
Jaqueline Bohrer Schuch
2,4
Received: 10 July 2017 /Accepted: 11 May 2018 /Published online: 1 June 2018
#
Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder characterized by impairments in social behaviors
and communication. Oxytocin and its signaling pathway are related to a range of human behaviors, from facial expression
recognition to aggressive behaviors, and have been suggested as involved in the etiology of ASD. Our aim was to evaluate the
influence of two polymorphisms (rs1042778, rs53576) at the oxytocin receptor gene (OXTR) on ASD diagnosis and on specific
ASD-related clinical symptoms (seizures, panic, and aggressive behaviors). We also assessed if these SNPs could be related to
changes in OXTR availability and functionality using a bioinformatic approach. The sample was composed by 209 probands
with ASD and their biological parents. Family-based approach and logistic regression models were used to investigated the
outcomes. We observed that panic and aggressive behaviors were nominally associated with presence of rs1042778 T allele (P =
0.019/P
corr
= 0.114; P =0.046/P
corr
= 0.276 respectively). Also, in the family-based analysis, a trend towards association with
ASD susceptibility was observed for rs1042778 (G allele) (P = 0.066). In a bioinformatic approach, we demonstrated that
rs1042778 G allele is determinant for the binding of the transcription factor MAZ, suggesting that when the T allele is present,
the absence of MAZ binding might be associated with lower transcription levels of the OXTR gene. The overall findings suggest
that the OXTR gene may play a role in ASD diagnosis and some of its clinical phenotypes, supported by previous animal and
clinical studies. Further investigations are necessary to replicate our findings and fully understand the effects of the oxytocin
pathway on ASD.
Keywords Autism
.
Oxytocin receptor gene
.
Panic
.
Aggressive
.
Oxytocin
.
Endophenotype
Introduction
Oxytocin is a neuro-active hormone extensively involved in
several processes from childbirth to postnatal period, includ-
ing contraction during labor’s stages and breastfeeding
(Takayanagi et al. 2005; Uvnäs Moberg and Prime 2013). In
addition, oxytocin influence extends to other behaviors, being
important in parental care, romantic attachment, social inter-
action, and facial expression recognition (Andari et al. 2010;
Marazziti et al. 2006; Guastella et al. 2010; Lee et al. 2009;
Zhang et al. 2017b). Considering oxytocin pleiotropic effects
and its effects in the central nervous system (CNS), recent
studies have also investigated the role of the oxytocin signal-
ing pathway in behavioral and neuropsychiatric disorders.
Previous investigations have employed strategies involving
associated molecules, such as the oxytocin receptor (OXTR)
to assess oxytocin’s influence in different behaviors (Feldman
et al. 2015). OXTR is a G protein-coupled receptor (GPCR)
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s12031-018-1088-0) contains supplementary
material, which is available to authorized users.
* Jaqueline Bohrer Schuch
jaqbs.bio@gmail.com
1
Department of Basic Health Sciences, Universidade de Ciências da
Saúde de Porto Alegre, Porto Alegre, Brazil
2
Department of Genetics, Instituto de Biociências, Universidade
Federal do Rio Grande do Sul, Porto Alegre, Brazil
3
Child Neurology Unit, Hospital de Clínicas de Porto Alegre,
Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
4
Laboratory of Immunosenescence, Graduate Program in Biomedical
Gerontology, Pontifícia Universidade Católica do Rio Grande do Sul,
Porto Alegre, Brazil
Journal of Molecular Neuroscience (2018) 65:213–221
https://doi.org/10.1007/s12031-018-1088-0
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