Arginine Vasopressin Receptor 1A Gene Research Articles

Serum Copeptin, Perceived Stress, and Pain in Patients Living with Sickle Cell Disease

Sickle cell disease (SCD) is a hereditary blood disorder characterized by intense acute and chronic pain episodes, resulting in a complex interplay of negative physical and emotional experiences. One of the main barriers to addressing pain in this disease state is the limited information about the mechanisms affecting the variable degree and types of pain and stress that impact patients in this population. The arginine vasopressin receptor1a gene (AVPR1A) single nucleotide polymorphism (rs10877969) is associated with aspects of acute pain and stress related pain in patients living with SCD. Arginine vasopressin (AVP) is a hormone known for its role in regulating extracellular fluid, vasoconstriction, and the endocrine stress response. However, due to its short half-life, AVP is difficult to measure. Thus, copeptin, the stable biologically inactive C-terminal portion of pro-vasopressin, is often used as a surrogate marker for AVP secretion. Copeptin is a marker of hypothalamic-pituitary-adrenal axis activation, however, its levels have not been studied in patients living with SCD. Psychological stress has been associated with changes in circulating copeptin concentrations. Considering the relationship between pain, stress, and copeptin, it is important to investigate their relationship in the context of SCD. The primary objective of this study was to examine serum copeptin levels with reports of perceived stress and pain in this patient population. In this cross-sectional study, we investigated serum copeptin levels, perceived stress, and pain experiences in a cohort of 50 adults living with SCD. Th participants had a mean age of 39.8±8.5 years, ranging from 29 to 59 years. Ninety-six percent of the participants were of African ancestry and 62% were female. Participants had the following hemoglobin genotypes: 68% had SS, 24% had SC, and 8% had other Hgb genotypes. To assess pain experiences, participants responded to questionnaires, including the Average Pain Intensity (API, average of current, least, and worst pain experienced within a 24-hour period, measured on a scale from 0 to 10). The Adult Sickle Cell Quality of Life Measure (ASCQ-Me) was used to measure number of vaso-occlusive crises (VOC). Perceived stress was assessed using the Perceived Stress Scale (PSS). Serum copeptin levels were quantified using a well-established laboratory. All the participants provided blood samples and completed psychological scales. Descriptive statistics and bivariate associations were conducted using R statistical software package. The study received approval from the Institutional Review Board at the University of Tennessee Health Science Center. We observed no significant differences in mean copeptin levels by sex ( p=.33) or associations between copeptin levels and age ( p=.66), weight ( p=.81), number of hospitalizations due to pain crisis ( p=.23), and the number of pain crisis managed at home ( p=0.07). The coefficients for API .92 ( p=.05) and PSS .97 ( p=.03) exhibited statistically significant positive association with copeptin levels. Our findings provide insights into the relationship between serum copeptin levels, perceived stress, and pain intensity in patients with sickle cell disease (SCD). The positive associations observed between copeptin levels and both perceived stress and average pain intensity underscore the potential interchange of pain and psychological stress in the regulation of copeptin secretion in this patient population. Our results indicate that copeptin levels are not significantly influenced by sex, age, or weight suggesting that these demographic factors may not be major determinants of copeptin viability in patients living with SCD. While sickle cell severity indicators did not show significant associations with copeptin levels, further investigation with larger sample sizes is needed to validate these findings and explore additional factors contributing to pain and psychological stress in individuals living with SCD. Ultimately, understanding the complexities of copeptin regulation may lead to improved pain management strategies and enhanced overall well-being for patients with this challenging disorder.

Acute Liver Failure: Biomarkers Evaluated by the Acute Liver Failure Study Group.

There has been a growing interest in identifying prognostic biomarkers that alone or with available prognostic models (King's College Criteria, KCC; MELD and ALFSG Prognostic Index) would improve prognosis in acute liver failure (ALF) patients being assessed for liver transplantation. The Acute Liver Failure Study Group (ALFSG) has evaluated 15 potential prognostic biomarkers: serum AFP; apoptosis-associated proteins; serum actin-free Gc-globulin; serum glycodeoxycholic acid; sRAGE/RAGE ligands; plasma osteopontin; circulating MBL, M-, L-, H-ficolin and CL-1; plasma galectin-9; serum FABP1; serum Lct2; miRNAs; factor V; thrombocytopenia, and sCD163. The ALFSG also has reported on 4 susceptibility biomarkers: keratins 8 and 18 (K8/K18) gene variants; polymorphisms of genes encoding putative APAP-metabolizing enzymes ( UGT1A1 , UGT 1A0 , UGT 2B15 , SULT1A1 , CYP2E1 , and CYP3A5 ) as well as CD44 and BHMT1 ; single nucleotide polymorphisms (SNPs) of genes associated with human behavior, rs2282018 in the arginine vasopressin ( AVP ) gene and rs11174811 in the AVP receptor 1A gene. Finally, rs2277680 of the CSCL16 gene in HBV-ALF patients. In conclusion, we have reviewed the prognostic and susceptibility biomarkers studied by the ALFSG. We suggest that a better approach to predicting the clinical outcome of an ALF patient will require a combination of biomarkers of pathogenic processes such as cell death, hepatic regeneration, and degree of inflammation that could be incorporated into prognostic models such as KCC, MELD or ALFSG PI.

Analysis of AVPR1A, thermal and pressure pain thresholds, and stress in sickle cell disease.

In patients with sickle cell disease (SCD), negative physical and emotional experiences result from intense chronic and acute pain episodes, but factors underlying these, and their interactions, are not well understood. The arginine vasopressin receptor 1a gene (AVPR1A) single nucleotide polymorphism rs10877969 has been previously associated with aspects of acute pain and stress related pain. In this study, we tested for associations between this SNP, thermal and pressure pain thresholds, clinical pain, and stress in people with SCD. 150 adults enrolled with SCD completed pain intensity measures (Average Pain Intensity, API) and the Perceived Stress Questionnaire (PSQ). Thermal and pressure pain threshold data were available from quantitative sensory testing (QST), and rs10877969 genotypes were obtained. In models adjusted for age and gender, between rs10877969 genotypes, we observed no significant differences in thermal (cold, p = 0.66; heat, p = 0.91) and mechanical (pressure, p = 0.33) pain thresholds. The association of rs10877969 with API (p = 0.09) was borderline, but non-significant with PSQ (p = 0.51). The correlation between clinical pain and environmental stress was significant, r = 0.18, p = 0.024, however, the interaction of genotype and PSQ was not significant (p = 0.63). Clinical and experimental pain were not significantly associated with the rs10877969 genotype. The rs10877969 genotype did not moderate the correlation between environmental stress and clinical pain in this population. However, a trend toward a protective T allele effect on average pain rating in SCD warrants future exploration of this SNP/gene in SCD.

P-079: AVPR1A AND STRESS IN YOUNGER AND OLDER ADULTS WITH CHRONIC PAIN OF SICKLE CELL DISEASE

Purpose: Background: In patients with sickle cell disease (SCD), pain results in varied physical and emotional consequences. Insufficient information about underlying mechanisms affecting pain remains a barrier to addressing SCD pain. Multiple biological and psychological factors (i.e., environmental stress) known to contribute to other pain conditions are understudied in SCD where the median survival (38 years for men and 42 years for women) is lower than the general population. Emotional stress has been shown to be a trigger of pain in patients with SCD. Genetics plays an important but still not fully-understood role in the variation of pain. The rs10877969 SNP in the Arginine vasopressin receptor 1A gene (AVPR1A) is associated with aspects of acute pain and stress-related to pain, but it is unknown whether the genotype frequency differs between those younger or older than the median survival age for SCD. Our aim was to determine the association between AVPR1A genotype with stress and age in adults with SCD who had chronic pain. Materials and methods: Materials and methods: In a cross-sectional study, 169 participants with SCD and chronic pain (100% African descent; 62% female, mean age 36.4±11.6 years [younger adults n =110, 18-39 years and older adults n=59, ≥40 years]), we used the Perceived Stress Questionnaire (PSQ). As a part of a larger study, we genotyped samples using the Axiom Precision Medicine Research Array. We used the Michigan Imputation server to examine our single nucleotide polymorphism (SNP) of interest, rs10877969. The SNP was evaluated as the imputed score was R2>0.8. We used ANOVA to compare stress by genotype and age (younger and older adults). Results: Results: The rs10877969 genotype frequency for the overall sample was: CC 47 (28%), CT 72 (43%), and TT 50 (30%). The genotype frequency was similar for older adults vs. younger adults: CC 16 (27%) vs. 31 (28%), CT 24 (41%) vs. 48 (44%), and TT 19 (32%) vs. 31 (28%). Mean stress scores were not significantly different by genotype: CC mean = 0.39 ± 0.16, CT mean = 0.41 ± 0.19, and TT mean = 0.36 ± 0.16, p=0.22. Mean stress scores also were not significantly different by genotype for younger adults: CC mean = 0.39 ± 0.15, CT mean = 0.44 ± 0.19, and TT mean = 0.36 ± 0.14, p=0.09 or older adults: CC mean = 0.37 ± 0.19, CT mean = 0.34 ± 0.16, TT mean = 0.34 ± 0.19, p=0.90. Mean stress scores were significantly lower (p<0.05) for the older adults (mean = 0.35 ± 0.18) than the younger adults (mean = 0.41 ± 0.17). Conclusion: Discussion-Conclusion: Younger adults had higher average stress than older adults. In contrast to prior research, in this study there was not an association between genotype and stress. Previously, the stand-out result was that individuals with SCD and CC genotype cited stress much less than the other two genotypes. The current result has a very different pattern. Further research is needed to examine stress and the rs10877969 genotype using other indicators of stress in this population. The authors do not declare any conflict of interest

AVPR1A and Stress in Adults With Sickle Cell Disease–Related Chronic Pain

Purpose: Emotional stress is a known pain trigger in patients with sickle cell disease (SCD). The Arginine vasopressin receptor 1A gene (AVPR1A), SNP rs10877969, is associated with acute pain and stress-related pain. Our study investigated the association between AVPR1A genotype with stress and age in adults with SCD pain. Methods: 169 participants with SCD and chronic pain (100% African descent; mean age 36.4 ± 11.6 years [range =18-74 years]) completed the Perceived Stress Questionnaire. The SNP was evaluated as the imputed score was R2>0.8. ANOVA compared stress by genotype and age. Findings: Mean stress scores were significantly lower (p<0.05) for the older adults (0.35 ± 0.18) than the younger adults (0.41 ± 0.17). Mean stress scores were not significantly different by genotype for younger or older adults. Discussion: The rs10877969 genotype frequency was not different by age. In contrast to prior research, there was no association between genotype and stress.

Vasopressin SNP pain factors and stress in sickle cell disease.

PurposeFrequencies of single nucleotide polymorphisms (SNPs) from pain related candidate genes are available for individuals with sickle cell disease (SCD). One of those genes, the arginine vasopressin receptor 1A gene (AVPR1A) and one of its SNPs, rs10877969, has been associated with pain and disability in other pain populations. In patients with SCD, clinical factors such as pain and stress have been associated with increased health care utilization, but it is not known if the presence of the AVPR1A SNP plays a role in this observation. The study purpose was to explore the relationships between rs10877969 and self-reported pain, stress, and acute care utilization events among individuals with SCD.MethodsIn a cross-sectional investigation of outpatients with SCD, participants completed PAINReportIt®, a computerized pain measure, to describe their pain experience and contributed blood or saliva samples for genetic analysis. We extracted emergency department and acute care utilization from medical records.ResultsThe SNP genotype frequencies (%) for this sample were CC 30 (28%), CT 44 (41%), TT 33 (31%). Acute care utilization and stress as an aggravator of pain were significantly associated with the rs10877969 genotype (p = .02 and p = .002, respectively). The CT genotype had the highest mean utilization and CC genotype was associated with not citing stress as a pain aggravator. Chronic pain was not associated with rs10877969 (p = .41).ConclusionThis study shows that rs10877969 is related to indicators of stress and acute pain. Further research is recommended with other measures of stress and acute pain.

Promoter methylation changes and vascular dysfunction in pre-eclamptic umbilical vein

BackgroundHypertension is one of primary clinical presentations of pre-eclampsia. The occurrence and progress of hypertension are closely related to vascular dysfunction. However, information is limited regarding the pathological changes of vascular functions in pre-eclamptic fetuses. Human umbilical cord vein was used to investigate the influence of pre-eclampsia on fetal blood vessels in this study.ResultsThe present study found that the vasoconstriction responses to arginine vasopressin (AVP) and oxytocin (OXT) were attenuated in the pre-eclamptic umbilical vein as compared to in normal pregnancy, which was related to the downregulated AVP receptor 1a (AVPR1a), OXT receptor (OXTR), and protein kinase C isoform β (PKCβ), owing to the deactivated gene transcription, respectively. The deactivated AVPR1a, OXTR, and PKCB gene transcription were respectively linked with an increased DNA methylation within the gene promoter.ConclusionsTo the best of our knowledge, this study first revealed that a hyper-methylation in gene promoter, leading to relatively reduced patterns of AVPR1a, OXTR, and PKCB expressions, which was responsible for the decreased sensitivity to AVP and OXT in the umbilical vein under conditions of pre-eclampsia. The data offered new and important information for further understanding the pathological features caused by pre-eclampsia in the fetal vascular system, as well as roles of epigenetic-mediated gene expression in umbilical vascular dysfunction.

Correlation between miRNA target site polymorphisms in the 3' UTR of AVPR1A and the risk of hypertension in the Chinese Han population.

We aimed to study the relationship between rs11174811 and rs3803107 single nucleotide polymorphisms (SNPs) in miRNA target sites of the 3′ UTR in the arginine vasopressin receptor 1a gene (AVPR1A) and the risk of hypertension in the Chinese Han population. The genotypes at rs11174811 and rs3803107 were analyzed by direct sequencing in 425 Chinese Han patients with hypertension and 425 healthy subjects. AVPR1A expression was investigated by transfecting miR-526b, miR-375, and miR-186 mimics into human umbilical vein endothelial cells (HUVECs) containing AVPR1A rs11174811 CC, CA/AA and AVPR1A rs3803107 GG, GA/AA genotypes. The A alleles of rs11174811 (adjusted OR = 1.424, 95% CI: 1.231–1.599, P<0.001) and rs3803107 (adjusted OR = 1.222, 95% CI: 1.092–1.355; P=0.001) were high risk factors for hypertension. Plasma levels of miR-526b, miR-375, and miR-186 were higher in the study group than in the control group (P<0.001). The expression levels of AVPR1A mRNA in AVPR1A rs11174811 and rs3803107 mutant HUVECs were higher than those in wild-type cells (t = 8.811, 4.068 and P=0.001, 0.015, respectively). The single nucleotide polymorphisms rs11174811 and rs3803107 in the AVPR1A gene are associated with an increased risk of hypertension in the Chinese Han population. This may be related to the effect of these variants on the regulation of AVPR1A expression by miRNAs.

Abstract A063: Preclinical evaluation of an arginine vasopressin receptor 1A (AVPR1A) antagonist in castration-resistant prostate cancer

Abstract Background: Advanced prostate cancer is treated by androgen deprivation, but despite initial responses most tumors inevitably recur. The recurrent disease is termed castration-resistant prostate cancer (CRPC) and is characterized by active androgen receptor (AR) signaling despite decreased androgen levels. AR activity in CRPC occurs through a variety of mechanisms including upregulation of AR coactivators, such as Vav3, and expression of constitutively active AR variants, which lack the ligand binding domain and are linked to poor prognosis. We previously demonstrated that PC cells are growth inhibited by depletion of either Vav3 or the clinically prevalent AR variant, AR-V7 (1). Gene expression profiling in CRPC cells revealed that arginine vasopressin receptor 1a (AVPR1a) was significantly reduced by depletion of either Vav3 or AR-V7. AVPR1a is a G protein-coupled receptor that has not been previously linked to PC. Analysis of publicly available datasets showed that the AVPR1a gene exhibits a significant increase in copy number in human CRPC specimens and AVPR1a mRNA is upregulated in aggressive PC (2-4). Methods: To explore the role of AVPR1a in PC cells, we selectively depleted AVPR1a in a panel of prostate cancer and prostate epithelial cell lines and examined cell survival and proliferation in culture and soft agar, as well as cell migration and invasion. Conversely, we overexpressed AVPR1a in an androgen-dependent PC cell line, LNCaP, and examined growth in vitro and in vivo in androgen-depleted conditions. We investigated AVPR1a antagonism in two distinct in vivo models of CRPC progression and growth using an effective and safe-in-humans AVPR1a antagonist, relcovaptan. Results: We showed that depletion of AVPR1a greatly inhibited the proliferation of multiple CRPC cell lines but had less to no effect on androgen-dependent PC cells or nontumorigenic prostate epithelial cells. Depletion of AVPR1a also decreased CRPC cell anchorage-independent growth. Conversely, overexpression of AVPR1a in androgen-dependent LNCaP cells conferred castration resistance in vitro and in vivo. Similar to depletion of AVPR1a, treatment of PC cells with the AVPR1a antagonist relcovaptan decreased CRPC anchorage-independent growth. AVPR1a depletion or antagonism was also effective at decreasing CRPC metastatic properties: migration and invasion. In a preclinical xenograft model of progression to castration resistance, we found that relcovaptan halted tumor growth and stabilized circulating levels of a clinical tumor progression marker, prostate specific antigen (PSA). We evaluated relcovaptan efficacy on end-stage metastatic CRPC growth. C4-2B CRPC cells were injected into the tibias of castrated mice to model tumor growth and bone remodeling. Relcovaptan significantly inhibited tumor growth and prevented cancer cell-induced bone remodeling. Conclusion: AVPR1a is a promising new therapeutic target against CRPC. We propose that AVPR1a antagonists may be repurposed for PC therapy.

Sex-specific mediation effect of the right fusiform face area volume on the association between variants in repeat length of AVPR1A RS3 and altruistic behavior in healthy adults.

Microsatellite variants in the arginine vasopressin receptor 1A gene (AVPR1A) RS3 have been associated with normal social behaviors variation and autism spectrum disorders (ASDs) in a sex-specific manner. However, neural mechanisms underlying these associations remain largely unknown. We hypothesized that AVPR1A RS3 variants affect altruistic behavior by modulating the gray matter volume (GMV) of specific brain regions in a sex-specific manner. We investigated 278 young healthy adults using the Dictator Game to assess altruistic behavior. All subjects were genotyped and main effect of AVPR1A RS3 repeat polymorphisms and interaction of genotype-by-sex on the GMV were assessed in a voxel-wise manner. We observed that male subjects with relatively short repeats allocated less money to others and exhibited a significantly smaller GMV in the right fusiform face area (FFA) compared with male long homozygotes. In male subjects, the GMV of the right FFA exhibited a significant positive correlation with altruistic behavior. A mixed mediation and moderation analysis further revealed both a significant mediation effect of the GMV of the right FFA on the association between AVPR1A RS3 repeat polymorphisms and allocation sums and a significant moderation effect of sex (only in males) on the mediation effect. Post hoc analysis showed that the GMV of the right FFA was significantly smaller in male subjects carrying allele 426 than in non-426 carriers. These results suggest that the GMV of the right FFA may be a potential mediator whereby the genetic variants in AVPR1A RS3 affect altruistic behavior in healthy male subjects. Hum Brain Mapp 37:2700-2709, 2016. © 2016 Wiley Periodicals, Inc.

Editorial: Individual differences: from neurobiological bases to new insight on approach and avoidance behavior.

Editorial: Individual differences: from neurobiological bases to new insight on approach and avoidance behavior.

A new measure for the revised reinforcement sensitivity theory: psychometric criteria and genetic validation.

Jeffrey Gray's Reinforcement Sensitivity Theory (RST) represents one of the most influential biologically-based personality theories describing individual differences in approach and avoidance tendencies. The most prominent self-report inventory to measure individual differences in approach and avoidance behavior to date is the BIS/BAS scale by Carver and White (1994). As Gray and McNaughton (2000) revised the RST after its initial formulation in the 1970/80s, and given the Carver and White measure is based on the initial conceptualization of RST, there is a growing need for self-report inventories measuring individual differences in the revised behavioral inhibition system (BIS), behavioral activation system (BAS) and the fight, flight, freezing system (FFFS). Therefore, in this paper we present a new questionnaire measuring individual differences in the revised constructs of the BIS, BAS and FFFS in N = 1814 participants (German sample). An English translated version of the new measure is also presented and tested in N = 299 English language participants. A large number of German participants (N = 1090) also filled in the BIS/BAS scales by Carver and White (1994) and the correlations between these measures are presented. Finally, this same subgroup of participants provided buccal swaps for the investigation of the arginine vasopressin receptor 1a (AVPR1a) gene. Here, a functional genetic polymorphism (rs11174811) on the AVPR1a gene was shown to be associated with individual differences in both the revised BIS and classic BIS dimensions.

Association and Promoter Analysis of AVPR1A in Finnish Autism Families.

The arginine vasopressin receptor 1A gene (AVPR1A) is known to affect social communication and has been reported to associate with autism in several studies. Given that the microsatellite RS1 and a few SNPs in the promoter region of the AVPR1A have repeatedly associated with several traits, including autism it is rather surprising that the molecular explanation for these associations has remained unknown, although it has been reported that the allele length of the AVPR1A microsatellites might affect disease risk. Here we carried out an extended association analysis of three microsatellites and 12 tag single nucleotide polymorphisms (SNPs) in and around the AVPR1A gene in 205 Finnish families followed by promoter analysis. FBAT version v2.0.3 was used for family-based genetic association analyses of AVPR1A microsatellites and SNPs. The nearby microsatellite RS1 was found to harbor the best association. Interestingly, there are two potentially relevant transcription factor (TF) binding sites at RS1: for MEF2C and PBX, predicted with the Match algorithm in the TRANSFAC database. Sequence variations changing the affinity of these TFs might partly explain the AVPR1A promoter region associations shown in autism.

Genetic analysis of human extrapair mating: heritability, between-sex correlation, and receptor genes for vasopressin and oxytocin

As in other socially monogamous species, pair-bonded humans commonly engage in sex with a partner other than their primary mate. For men, extrapair mating is straightforwardly explained from an adaptive perspective in terms of the reproductive benefits of multiple mates. For women, whose reproductive output is limited by their reproductive biology rather than by their number of mates, the adaptive benefits of extrapair mating are less obvious. Dominant adaptive explanations focus on women obtaining genetic benefits for their offspring by mating with high-quality extrapair partners. Non-adaptive explanations have rarely been considered in humans, but recent findings in birds suggest that females' predisposition to extrapair mating may result from indirect selection, via direct selection on males and a between-sex genetic correlation. To examine the plausibility of this non-adaptive explanation of extrapair mating in women, we used data on recent extrapair mating in 7,378 Finnish twins and their siblings. Genetic modelling showed within-sex broad-sense heritability—i.e. the percentage of variation in extrapair mating due to genetic variation—of 62% in men and 40% in women. There was no between-sex correlation in extrapair mating, making indirect selection unlikely. Based on previous animal and human findings, we also tested for association of the arginine vasopressin receptor 1A gene (AVPR1A) and oxytocin receptor gene (OXTR) with extrapair mating. We found gene-based association for AVPR1A in women but not in men, and OXTR showed no significant association in either sex. Overall, these findings confirm genetic underpinnings of extrapair mating in humans, but do not suggest that women's predisposition to extrapair mating is due to selection on men.

Association between the arginine vasopressin receptor 1A (AVPR1A) gene and preschoolers’ executive functioning

Recent evidence implicates the arginine vasopressin (AVP) system in complex neuropsychological disorders which are characterized by deficits in executive functioning (EF). Despite the genetic contribution to EF, little is currently known about its molecular genetic basis. Drawing on research from social neuroscience and the role of related physiological systems in psychopathology, the current study hypothesized that variability in the AVP receptor 1a gene (AVPR1A) would be associated with EF in an epidemiological sample of 323 normally developing preschool-aged children. Using a family-based association design, the current study found that variability in the rs7298346 marker, located in the 5′-flanking region, was significantly related to a composite measure of EF in 4-year-old children after controlling for a variety of covariates and children’s theory of mind. The converse association between AVPR1A and theory of mind (after controlling for EF) was not significant, suggesting a level of specificity in this relationship. The results are discussed in terms of the difficulties faced by genetic association studies in teasing apart the behavioral phenotypes that characterize complex psychological diseases and the involvement of multiple physiological systems in human behavior.

Human maternal behaviour is associated with arginine vasopressin receptor 1A gene

Parenting is one of the main influences on children's early development, and yet its underlying genetic mechanisms have only recently begun to be explored, with many studies neglecting to control for possible child effects. This study focuses on maternal behaviour and on an allele at the RS3 promoter region of the arginine vasopressin receptor 1A (AVPR1A) gene, previously associated with autism and with higher amygdala activation in a face-matching task. Mothers were observed during a free-play session with each of their 3.5-year-old twins. Multilevel regression analyses revealed that mothers who are carriers of the AVPR1A RS3 allele tend to show less structuring and support throughout the interaction independent of the child's sex and RS3 genotype. This finding advances our understanding of the genetic influences on human maternal behaviour.

Variable number of tandem repeat polymorphisms of the arginine vasopressin receptor 1A gene and impulsive aggression in patients with borderline personality disorder

Variable number of tandem repeat polymorphisms of the arginine vasopressin receptor 1A gene and impulsive aggression in patients with borderline personality disorder

AVPR1A and SLC6A4 Polymorphisms in Choral Singers and Non-Musicians: A Gene Association Study

Amateur choral singing is a common pastime and worthy of study, possibly conferring benefits to health and social behaviour. Participants might be expected to possess musical ability and share some behavioural characteristics. Polymorphisms in genes concerned with serotonergic neurotransmission are associated with both behaviour and musical aptitude. Those investigated previously include the variable number tandem repeats RS1, RS3 and AVR in the AVPR1A (arginine vasopressin receptor 1a) gene and STin2 in the SLC6A4 (solute carrier family 6 [neurotransmitter transporter, serotonin], member 4) gene, as well as the SLC6A4 promoter region polymorphism, 5-HTTLPR. We conducted a genetic association study on 523 participants to establish whether alleles at these polymorphisms occur more commonly in choral singers than in those not regularly participating in organised musical activity (non-musicians). We also analysed tagging single nucleotide polymorphisms (SNPs) for AVPR1A and SLC6A4 to determine whether other variants in these genes were associated with singer/non-musician status. At the STin2 polymorphism, overall association with singer/non-musician status was evident at P = 0.006. The 9-repeat (P = 0.04) and 12-repeat (P = 0.04) alleles were more common in singers and the 10-repeat allele less so (P = 0.009). Odds ratios were 0.73 (95% CI 0.57–0.94) for the 10-repeat allele and 2.47 (95% CI 0.88–6.94) for the rarer 9-repeat allele. No overall association was detected at P<0.05 between any other polymorphism and singer/non-musician status. Our null findings with respect to RS3, RS1 and AVR, polymorphisms associated with musical ability by other authors, suggest that choir membership may depend partly on factors other than musical ability. In a related musical project involving one participating choir, a new 40-part unaccompanied choral work, “Allele”, was composed and broadcast on national radio. In the piece, each singer's part incorporated their personal RS3 genotype.

Functionality of promoter microsatellites of arginine vasopressin receptor 1A (AVPR1A): implications for autism

BackgroundArginine vasopressin (AVP) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. The arginine vasopressin receptor 1A gene (AVPR1A) is widely expressed in the brain and is considered to be a key receptor for regulation of social behaviour. Moreover, genetic variation at AVPR1A has been reported to be associated with autism. Evidence from non-human mammals implicates variation in the 5'-flanking region of AVPR1A in variable gene expression and social behaviour.MethodsWe examined four tagging single nucleotide polymorphisms (SNPs) (rs3803107, rs1042615, rs3741865, rs11174815) and three microsatellites (RS3, RS1 and AVR) at the AVPR1A gene for association in an autism cohort from Ireland. Two 5'-flanking region polymorphisms in the human AVPR1A, RS3 and RS1, were also tested for their effect on relative promoter activity.ResultsThe short alleles of RS1 and the SNP rs11174815 show weak association with autism in the Irish population (P = 0.036 and P = 0.008, respectively). Both RS1 and RS3 showed differences in relative promoter activity by length. Shorter repeat alleles of RS1 and RS3 decreased relative promoter activity in the human neuroblastoma cell line SH-SY5Y.ConclusionsThese aligning results can be interpreted as a functional route for this association, namely that shorter alleles of RS1 lead to decreased AVPR1A transcription, which may proffer increased susceptibility to the autism phenotype.

Genomic Scans Support Repetitive Continental Colonization Events during the Rapid Radiation of Voles (Rodentia: Microtus): the Utility of AFLPs versus Mitochondrial and Nuclear Sequence Markers

Single locus studies might not resolve phylogenetic relationships and the evolutionary history of taxa. The analysis of multiple markers promises higher resolution, and congruence among loci may indicate that the phylogenies represent the underlying species history. Here, we examine the utility of a genome-wide approach based on amplified fragment length polymorphisms (AFLP) and several DNA sequence markers in resolving phylogenetic signals in the rapidly radiating rodent genus Microtus which produced about 70 vole species within the last 1.2-2 myr. The current Holarctic distribution of Microtus is assumed to have resulted from three independent colonization events out of Asia to North America, Europe, and northern Asia without subsequent colonization, which would have led to deep splits between species from different continents. We investigated this hypothesis of three single colonization events by reconstructing the phylogenetic relationships among species from all three continents based on data from the first exon of the nuclear arginine vasopressin receptor 1a gene (EXON1), an adjacent noncoding region and the mitochondrial cytochrome b gene. The phylogenetic patterns obtained from these sequence markers are contrasted to genome-wide data on more than 1800 amplified fragment length polymorphisms (AFLP) analyzed for the same samples. Our results show that the single sequence markers partially resolve the phylogenetic relationships within Microtus, but with some incongruence mostly between EXON1 and the other loci. However, deeper nodes of the radiation are only weakly supported and neither the combination of the markers nor additional nuclear sequences improved the resolution significantly. AFLPs provided much stronger support for major continent-specific clades, and show also that reciprocal monophyly of American and European voles is incomplete. Our results demonstrate that Microtus voles colonized the American and European continents each repeatedly in several independent events on similar colonization routes during their radiation. More generally, this study supports the suitability of AFLPs as an alternative to sequence markers to resolve the evolutionary history of rapidly radiating taxa.