OBJECTIVE: We studied gene-environment, as well as gene-gene interaction to elucidate their effects on symptom severity and predict clinical outcomes in functional neurological disorders (FND).
METHODS: Eighty-five patients with mixed FND were genotyped for ten single-nucleotide polymorphisms (SNP) from seven different stress-related genes. We tested cross-sectionally the association between genotype and the symptomatology of FND (symptom severity assessed with the examiner-based clinical global impression score [CGI] and age of onset). Clinical outcome was assessed in 52 patients who participated in a follow-up clinical visit after eight months (following their individual therapies as usual). We tested longitudinally the association between genotype and clinical outcome in FND. We examined the contribution of each SNP and their interaction between them to FND symptomatology and outcome.
RESULTS: We identified a nominal association between tryptophan hydroxylase 1 (TPH1) rs1800532 and symptom severity (CGI1) in FND under a codominant model (T/T: ßT/T = 2.31, seT/T = 0.57; G/T: ßG/T = -0.18, seG/T = 0.29, P = 0.035), with minor allele (T) carriers presenting more severe symptoms. An association was identified between TPH1 and clinical outcome, suggesting that major allele (G) carriers were more likely to have an improved outcome under a codominant model (G/T: ORG/T = 0.18, CIG/T = [0.02-1.34]; T/T: ORT/T = 2.08, CIT/T = [0.30-14.53], P = 0.041). Our analyses suggested a significant gene-gene interaction for TPH2 (rs4570625) and OXTR (rs2254298) on symptom severity, and a significant gene-gene interaction for TPH1, TPH2 and BDNF (rs1491850) on clinical outcome.
CONCLUSIONS: FND might arise from a complex interplay between individual predisposing risk genes involved in the serotonergic pathway and their gene-gene interactions.

Oxytocin is a neuropeptide produced by magnocellular neurosecretory neurons located primarily in the supraoptic nucleus and paraventricular nucleus of the hypothalamus. The long axons of these neurons project to the neurohypophysis where oxytocin is released into the general circulation in response to the physiological demands. Oxytocin plays critical roles in female reproductive physiology, specifically in uterine contraction during labor and milk ejection while nursing. Oxytocin is also called \"the love hormone\" due to its modulatory roles in prosocial behaviors, including social recognition, maternal behavior, and pair bonding. Oxytocin influences behaviors by binding to oxytocin receptors (OXTR) located in various parts of the brain. Previously, we discovered a group of estrogen-dependent OXTR neurons that is exclusively present in the anteroventral periventricular nucleus (AVPV) of females but not of males. The female-specific expression of OXTR in the AVPV is a rare case of neurochemically-demonstrated, all-or-none sexual dimorphism in the brain. In this review, the cellular characterization and functional significance of the sexually dimorphic OXTR neurons in the AVPV as well as the clinical implications of the research will be discussed.

Postpartum depression (PPD) is a common illness in mothers after childbirth. PPD negatively affect the mother\'s quality of life and the bond with the infant, which can interfere with the infant\'s emotional, social, and cognitive development. PPD is caused by various biological and psychosocial factors. The aim of this review is to summarize the latest evidence of the associations between genetic polymorphisms and PPD. PubMed and Scopus were used as the literature search databases for this review. The keywords used were postpartum depression, postnatal depression, genetic, and polymorphism. Twenty-seven articles were reviewed after screening and applying the inclusion criteria. As results, the serotonin gene (5-HTTLPR) and oxytocin genes (OXTR) have the most significant associations with PPD among other genes. Further research on PPD biomarkers should be conducted to diagnose and treat PPD patients.

DNA sequence variation and altered epigenetic regulation of the oxytocin receptor gene (OXTR) have been implicated in autism and autistic-like behaviors. While previous studies have examined subsegments of OXTR, nanopore Cas9-targeted sequencing (nCATS) allows deep characterization of entire genes with simultaneous assessment of epigenetic 5-methylcytosine (5mC) modification and without the need for prior DNA amplification or bisulfite conversion. This pilot study uses an nCATS approach to sequence the entire OXTR gene and its regulatory construct and screen for 5mC modification to compare results between individuals with high-functioning autism (HFA) and neurotypical controls (NC).
Using DNA extracted from peripheral blood, OXTR (Hg38, chr3: 8750381-8770434, 20,054 base pairs) was analyzed by nCATS. 5mC modification probabilities were calculated and visualized across the gene and differential methylation analysis was performed.
Twenty adults with HFA (10 males, 10 females) and 20 age- and sex-matched NC (± 5 years) were included. There were no apparent group differences in the entire OXTR gene sequence, except for the intron variant rs918316, which was clustered in the HFA group. However, differential methylation analysis did not reveal a single significant group-dependent differentially methylated site among the 412 CpG sites captured.
Limitations of this study include the small number of samples due to the pilot nature of the study, which particularly limits the relevance of the sequence variants found. It should also be noted that the use of peripheral blood material limits the ability to draw conclusions about central processes.
Previous findings of autism-associated OXTR epigenetic alterations were not reproducible with our method. In our opinion, this may lead to a reconsideration of the relevance of altered methylation at individual OXTR CpG positions in autism research. However, given the pilot nature of the study, these results need to be replicated in independent cohorts and with larger sample sizes.

A socioeconomic crisis in Russia lasted from 1991 to 1998 and was accompanied by a sharp drop in the birth rate. The main factor that influenced the refusal to have children during this period is thought to be prolonged social stress.
comparing frequencies of common gene variants associated with stress-induced diseases among generations born before, after, and during this crisis may show which genes may be preferred under the pressure of natural selection during periods of increased social stress in urban populations.
In the \"crisis\" group, a statistically significant difference from the other two groups was found in rs6557168 frequency (p = 0.001); rs4522666 was not in the Hardy-Weinberg equilibrium in this group, although its frequency did not show a significant difference from the other groups (p = 0.118). Frequencies of VNTRs in SLC6A3 and MAOA as well as common variants rs17689918 in CRHR1, rs1360780 in FKBP5, rs53576 in OXTR, rs12720071 and rs806377 in CNR1, rs4311 in ACE, rs1800497 in ANKK1, and rs7412 and rs429358 in APOE did not differ among the groups.
a generation born during a period of prolonged destructive events may differ from the rest of the gene pool of the population in some variants associated with personality traits or stress-related disorders.

The neurobiological systems of maintenance and control of behavioral responses result from natural selection. We have analyzed the selection signatures for single nucleotide variants (SNV) of the genes of oxytocin (OXT, OXTR) and vasopressin (AVP, AVPR1A, AVPR1B) systems, which are associated with the regulation of social and emotional behavior in distinct populations. The analysis was performed using original WGS (whole genome sequencing) data on Eastern Slavs (SlEast), as well as publicly available data from the 1000 Genomes Project on GBR, FIN, IBR, PUR, BEB, CHB, and ACB populations (the latter were taken as reference). To identify selection signatures, we rated the integrated haplotype scores (iHS), the numbers of segregating sites by length (nSl), and the integrated haplotype homozygosity pooled (iHH12) measures; the fixation index Fst was implemented to assess genetic differentiation between populations. We revealed that the strongest genetic differentiation of populations was found with respect to the AVPR1B gene, with the greatest differentiation observed in GRB (Fst = 0.316) and CHB (Fst = 0.325) in comparison to ACB. Also, high Fst values were found for SNVs of the AVPR1B gene rs28499431, rs33940624, rs28477649, rs3883899, and rs28452187 in most of the populations. Selection signatures have also been identified in the AVP, AVPR1A, OXT, and OXTR genes. Our analysis shows that the OXT, OXTR, AVP, AVPR1A, and AVPR1B genes were subject to positive selection in a population-specific process, which was likely contributing to the diversity of adaptive emotional response types and social function realizations.

Maternal care is crucial for the survival and development of offspring. Oxytocin modulates maternal behavior by binding to oxytocin receptors (OXTRs) in various parts of the brain. Previously, we showed that OXTRs are expressed in the anteroventral periventricular nucleus (AVPV) of female, but not male mice. Because the AVPV is involved in the regulation of maternal behavior and oxytocin enhances its induction, this finding leads to the hypothesis that the female specific population of OXTR neurons in the AVPV regulates maternal behavior. To address this hypothesis, OXTR-Venus reporter mice were used to assess if expression levels of OXTR in the AVPV are changed during the postpartum period. The total number of OXTR-Venus neurons was significantly greater in postpartum dams compared to virgin females. To assess efferent projections of the AVPV-OXTR neurons, a Cre-dependent fluorescent protein (tdTomato) expressing a viral vector was injected into one side of the AVPV of female OXTR-Cre mice. Fibers expressing tdTomato were found in hypothalamic areas containing oxytocin neurons (the supraoptic and paraventricular nuclei) and the midbrain areas (the ventral tegmental area and periaqueductal gray) that are involved in the regulation of maternal motivation. To assess if activity of the AVPV-OXTR neurons is involved in the regulation of maternal behaviors, a chemogenetic approach was employed. Specific inhibition of activity of AVPV-OXTR neurons completely abolished pup retrieval and nest building behaviors. Collectively, these findings demonstrate that AVPV-OXTR neurons in postpartum female mice constitute an important node in the neural circuitry that regulates maternal behavior.

Oxytocin (OXT) is secreted in a large amount during the middle and late pregnancy. Except for the regulation of functions related to childbirth, OXT is involved in the regulation of cognition, social behavior, addiction, pain and so on. Our aim is to confirm the increase of OXT content in mice in late pregnancy is the main cause of itch during pregnancy and observe whether exogenously administered OXT can induce or increase itch sensitivity. The research shows that itch sensitivity of mice increased significantly in late pregnancy and basically returned to normal one day after delivery. The number of OXT-positive neurons in paraventricular nucleus (PVN) and the content of OXT in serum of the late pregnant mice increased significantly, and decreased sharply after delivery. Intradermal injection of low concentration of OXT (0.2 nmol/L) could not induce scratching behavior in mice, but high concentration of OXT (5 nmol/L, 10 nmol/L) could do this in a dose-dependent manner. Low concentration of OXT significantly increased the itch sensitivity to histamine. Intradermal injection of oxytocin receptor (OXTR) or arginine vasopressin-1a receptor (AVPR1A) antagonist did not affect histamine-induced scratching behavior, but both reversed the increase of itch sensitivity in late pregnant mice or the facilitated itch sensitivity by OXT. Study suggests that both endogenous and exogenous increases in OXT can increase the body\'s sensitivity to itch, and even induce itch directly. Pruritus during pregnancy is closely related to the increase of OXT content in vivo. In the periphery, the itch-promoting effect of OXT is mediated by OXTR and AVPR1A.

UNASSIGNED: Alcohol use disorder (AUD) is a common mental disorder characterized by repeated withdrawal episodes. Negative emotions during withdrawal are the primary factors affecting successful abstinence. Oxytocin is a critical modulator of emotions. OXTR, the oxytocin receptor, may also be a promising candidate for treating alcohol withdrawal symptoms. Previous studies indicated that people with different genotypes of OXTR rs2254298 were reported to suffer from more significant depressive or heightened anxiety symptoms when experiencing early adversity. The present study aims to explore the modulatory role of the polymorphism OXTR rs2254298 on mood disorders during alcohol withdrawal and to help researchers better understand and develop effective relapse prevention and interventions for alcohol use disorders.
UNASSIGNED: We recruited 265 adult Chinese Han men with AUD. Anxiety and depressive symptoms were measured using the Self-Rating Anxiety Scale and Self-Rating Depression Scale. Alcohol dependence levels were measured using Michigan Alcoholism Screening Test. Genomic DNA extraction and genotyping from participants\' peripheral blood samples.
UNASSIGNED: First, a multiple linear regression was used to set the alcohol dependence level, OXTR.rs2254298, interaction terms as the primary predictor variable, and depression or anxiety as an outcome; age and educational years were covariates. There was a significant interaction between OXTR rs2254298 and alcohol dependence level on anxiety (B = 0.23, 95% confidence interval [CI]: 0.01-0.45) but not on depression (B = -0.06, 95% CI: -0.30 - 0.18). The significance region test showed that alcohol-dependent men who are GG homozygous were more likely to experience anxiety symptoms than subjects with the A allele (A allele: β = 0.27, p < 0.001; GG homozygote: β = 0.50, p < 0.001). Finally, re-parameterized regression analysis demonstrated that this gene-environment interaction of OXTR rs2254298 and alcohol dependence on anxiety fits the weak differential susceptibility model (R2 = 0.17, F (5,259) = 13.46, p < 0.001).
UNASSIGNED: This study reveals a gene-environment interactive effect between OXTR rs2254298 and alcohol withdrawal on anxiety but not depression. From the perspective of gene-environment interactions, this interaction fits the differential susceptibility model; OXTR rs2254298 GG homozygote carriers are susceptible to the environment and are likely to experience anxiety symptoms of alcohol withdrawal.

The oxytocin system is well-known for its role in social bonding and reproduction. Recently, the oxytocin system was found to play other metabolic roles such as regulation of food intake, peripheral glucose uptake, and insulin sensitivity. Variants in OXTR gene have been associated with overeating, increased cardiovascular risk, and type 2 diabetes (T2D). We tested 20 microarray-derived single nucleotide polymorphisms in the OXTR gene in 212 Italian families with rich family history for T2D and found four novel and one previously reported variant suggestively significant for linkage and association with the risk of T2D. Our study has shed some light into the genetics of susceptibility to T2D at least in Italian families.