Oxytocin and Vasopressin Receptor Gene Polymorphisms: Role in Social and Psychiatric Traits

Abstract

Oxytocin (OXT) and arginine-vasopressin (AVP) are two phylogenetically conserved neuropeptides that have been implicated in a wide range of social behaviors. Although a large body of research, ranging from rodents to humans, has reported on the effects of OXT and AVP administration on affiliative and trust behaviors, and has highlighted the genetic contributions of OXT and AVP receptor polymorphisms to both social behaviors and to diseases related to social deficits, the consequences of peptide administration on psychiatric symptoms, and the impact of receptor polymorphisms on receptor function, are still unclear. Despite the exciting advances that these reports have brought to social neuroscience, they remain preliminary and suffer from the problems that are inherent to monogenetic linkage and association studies. As an alternative, some studies are using polygenic approaches, and consider the contributions of other genes and pathways, including those involving DA, 5-HT, and reelin, in addition to OXT and AVP; a handful of report are also using genome-wide association studies. This review summarizes findings on the associations between OXT and AVP receptor polymorphism, social behavior, and psychiatric diseases. In addition, we discuss reports on the interactions of OXT and AVP receptor genes and genes involved in other pathways (such as those of dopamine, serotonin, and reelin), as well as research that has shed some light on the impact of gene polymorphisms on the volume, connectivity, and activation of specific neural structures, differential receptor expression, and plasma levels of the OXT and AVP peptides. We hope that this effort will be helpful for understanding the studies performed so far, and for encouraging the inclusion of other candidate genes not explored to date.

Keywords: GWAS; SNP; SSR; dopamine; polygenic trait; psychiatric disorders; quantitative traits loci; serotonin.

Figure 1

OXT and AVP are two closely related nonapeptides that exert their action on central and peripheral targets. (A) OXT and AVP are synthesized in the PVN and the SON of the hypothalamus. The peptidergic neurons in these nuclei project axons to the posterior pituitary, from where the peptides are released into the circulation. They act as hormones on peripheral targets, having well-documented actions (uterine contraction and vasoconstriction, for instance). In addition, dendrites of neurons in the PVN and the SON release the peptides directly into the brain, where they act as neurotransmitters or neuromodulators, regulating complex social cognition and behaviors. (B) OXT and AVP differ in only two aminoacids: this schematic drawing shows that, whereas the aminoacid sequence of OXT (top) includes an isoleucine at the third and a leucine at the eighth position, that of AVP (bottom) includes a phenylalanine and an arginine in the corresponding positions. Both peptides contain a cyclic six aminoacid ring, because of the disulfide bond formed by two cysteine residues.

Figure 2

OXTR and AVPR are G-protein coupled receptor expressed in key structures of the brain. Their genes present characteristic polymorphisms associated with differences in human social (and pathological) behaviors. (A) In the human brain, OXTR is expressed in the basolateral amygdala, the anterior and ventromedial hypothalamus, the olfactory nucleus, the diagonal band of Broca, the septal nuclei and the anterior cingulate (left). Its gene (right) is located on chromosome 3p25.3 (approximate position indicated by red vertical line). It contains four exons and three introns, which include several known SNPs. (B) AVPR1A is expressed in the septal nuclei, the thalamus and the basal amygdaloid nucleus (left); the gene encoding this receptor (right) is located on chromosome 12q14 (approximate position indicated by red vertical line). As in the case for OXTR, it contains an intron before the exon that encodes the seventh transmembrane domain. The schematic includes the SNPs (in the case of OXTR) and SSRs (in the case of AVPR) that are reviewed in this article.