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Oxytocin appears to be centrally involved in socioemotional functioning, and is hypothesized to be relevant to the severe disruption in close relationships characteristic of borderline personality pathology. We examined whether a polymorphism of the oxytocin receptor gene (OXTR rs53576) interacts with quality of family functioning to predict borderline personality disorder (BPD) symptomatology in a sample of youth at age 20. A total of 385 youth from a longitudinal study of offspring of depressed or nondepressed mothers who were well characterized with respect to their family conditions and BPD symptomatology provided DNA for genotyping. Analyses revealed a significant moderation of the link between early family quality and later BPD symptoms by OXTR rs53576, and the pattern was consistent with differential susceptibility (plasticity). Whereas A-allele carriers had high levels of BPD symptoms under negative family conditions and low levels under positive conditions, GG homozygotes had average levels of BPD symptoms regardless of their family quality.

Borderline personality disorder (BPD) is a highly prevalent psychiatric disorder with high morbidity and mortality. Early theories ascribed an environmental etiology of BPD, but growing evidence supports a genetic vulnerability as well. The primary aim of this study was to systematically review genetic association studies focused on BPD. PubMed, ISI Web of Knowledge and PsycINFO databases were searched for studies published until December 2012. Meta-analyses were also performed when three or more studies reported genetic data on the same polymorphism. Data were analyzed with Cochrane Collaboration Review Manager Software (RevMan, version 5.0). Quality and publication bias were assessed. The systematic review of association studies examining genetic polymorphisms and BPD produced conflicting results. Meta-analyses were performed for three serotonergic polymorphisms: two common polymorphisms of the serotonin transporter gene (SLC6A4), the promoter insertion/deletion (5-HTTLPR) and the intron 2 VNTR (STin2 VNTR), and the rs1800532 (A218C) polymorphism of the tryptophan hydroxylase 1 gene (TPH1), all showing no association. No direct role of genetic polymorphisms was found in BPD. However, a few studies only are present in literature to draw definite conclusions. Further studies focusing on gene × gene and gene × environment interactions are needed to more deeply dissect the genetic role in the modulation of BPD., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A functional polymorphism (val158met) of the gene coding for Catechol-O-methyltransferase (COM) has been demonstrated to be related to processing of emotional stimuli. Also, this polymorphism has been found to be associated with pain regulation in healthy subjects. Therefore, we investigated a possible influence of this polymorphism on pain processing in healthy persons as well as in subjects with markedly reduced pain sensitivity in the context of Borderline Personality Disorder (BPD). Fifty females (25 patients with BPD and 25 healthy control participants) were included in this study. Genotype had a significant--though moderate--effect on pain sensitivity, but only in healthies. The number of val alleles was correlated with the BOLD response in several pain-processing brain regions, including dorsolateral prefrontal cortex, posterior parietal cortex, lateral globus pallidus, anterior and posterior insula. Within the subgroup of healthy participants, the number of val alleles was positively correlated with the BOLD response in posterior parietal, posterior cingulate, and dorsolateral prefrontal cortex. BPD patients revealed a positive correlation between the number of val alleles and BOLD signal in anterior and posterior insula. Thus, our data show that the val158met polymorphism in the COMT gene contributes significantly to inter-individual differences in neural pain processing: in healthy people, this polymorphism was more related to cognitive aspects of pain processing, whereas BPD patients with reduced pain sensitivity showed an association with activity in brain regions related to affective pain processing.

Background: Suicide prediction is a huge challenge for mental health workers. Structured interviews based on epidemiological and clinical factors don't show effectiveness for suicide prevention. Biological markers, such as 5-HTTLPR, could help for identification of potential suicide attempters., Methods: We evaluated 198 bipolar patients and 103 health controls, using a structured interview according to DSM-IV criteria. Genotyping, blind of clinical assessment for identification of S carriers and structured interviews were performed in order to describe clinical and epidemiological factors which could be associated with suicide behavior. Statistical analyses were calculated by the x(2) test and logistic regression model., Results: We found that 26.77% and 16.67% had a lifetime history of non violent suicide attempt and violent suicide attempt, respectively. The clinical factors associated with violent and non violent suicide attempt had several differences. Violent suicide attempters had an earlier illness onset and had a higher number of psychiatric comorbidities (borderline personality disorder, panic disorder and alcoholism). The frequency of S allele carriers was higher only in those patients who had made a violent suicide attempt in their lifetime (x(2)=16.969; p=0.0001). In a logistic regression model including these factors, S allele carrier (5-HTTLPR) was the only factor associated with violent suicide attempt., Limitations: Sample size and retrospective assessment of suicide behavior history are the limitations of this study., Conclusions: Our study showed that serotonin polymorphism (5-HTTLPR) is strongly associated with violent suicidal behavior in BD patients. If confirmed, our results could be an important step to create a genetic tool for long-term suicide prediction., (2009 Elsevier B.V. All rights reserved.)

Objective: We analyzed i) the effects of serious life events (SLE) on impulsive aggression, and ii) modulating effects of the COMT Val(158)Met polymorphism on the association between SLEs and impulsive aggression in borderline personality disorder (BPD)., Method: One hundred and twelve female BPD patients from Germany were included in this study. Impulsive aggression was assessed by the Buss-Durkee-Hostility Inventory (BDHI)., Results: Childhood sexual abuse was associated with lower BDHI sum score (P = 0.003). In COMT Val(158)Val carriers, but not in Val/Met and Met/Met carriers, childhood sexual abuse and the cumulative number of SLEs were associated with lower BDHI sum scores (P < 0.05)., Conclusion: This study analyzing a specific gene x environment interaction in female BPD patients suggests an association between SLEs and impulsive aggression, as well as a modulating effect of the COMT Val(158)Val genotype on the relation between SLEs and impulsive aggression.

Impulsive aggression belongs to the key features of borderline personality disorder (BPD). In the development of BPD, serious life events are known to play a major role. Acute and chronic stress has been suggested to inhibit hippocampal brain-derived neurotrophic factor (BDNF) synthesis and to mediate neural plasticity in response to adverse social experiences. Recently it has been reported that the frequency of violent suicide attempts is higher in adult suicide attempters reporting severe childhood sexual abuse and carrying the Val(66)Val genotype of the BDNF Val(66)Met polymorphism. In this study we analysed modulating effects of BDNF Val(66)Met polymorphism on the effects of physical maltreatment, rape and childhood sexual abuse on impulsive aggression. One hundred and fifty-nine BPD patients from Germany and of Caucasian descent were included. Impulsive aggression was assessed by the Buss-Durkee-Hostility Inventory (BDHI). Childhood sexual abuse accounted for 23.6% of the variance of BDHI sum score. Childhood sexual abuse decreased BDHI sum score in BDNF Val/Val carriers but not in Met carriers. In contrast to previous findings this study analysing a specific gene x environment interaction in BPD patients suggests a decreasing effect of childhood sexual abuse on impulsive aggression in BPD patients, particularly in BDNF Val/Val carriers. The interrelations between serious life events, impulsive aggression and the BDNF Val(66)Met polymorphism as well as their implication for BPD are far from understood and require further investigations.

Background: In the development of borderline personality disorder (BPD) both genetic and environmental factors have important roles. The characteristic affective disturbance and impulsive aggression are linked to imbalances in the central serotonin system, and most of the genetic association studies focused on serotonergic candidate genes. However, the efficacy of dopamine D2 receptor (DRD2) blocking antipsychotic drugs in BPD treatment also suggests involvement of the dopamine system in the neurobiology of BPD., Methods: In the present study we tested the dopamine dysfunction hypothesis of impulsive self- and other-damaging behaviors: borderline and antisocial traits were assessed by Structured Clinical Interview for Diagnosis (SCID) for DSM-IV in a community-based US sample of 99 young adults from low-to-moderate income families. For the BPD trait analyses a second, independent group was used consisting of 136 Hungarian patients with bipolar or major depressive disorder filling out self-report SCID-II Screen questionnaire. In the genetic association analyses the previously indicated polymorphisms of the catechol-O-methyl-transferase (COMT Val158Met) and dopamine transporter (DAT1 40 bp VNTR) were studied. In addition, candidate polymorphisms of the DRD2 and DRD4 dopamine receptor genes were selected from the impulsive behavior literature., Results: The DRD2 TaqI B1-allele and A1-allele were associated with borderline traits in the young adult sample (p = 0.001, and p = 0.005, respectively). Also, the DRD4 -616 CC genotype appeared as a risk factor (p = 0.02). With severity of abuse accounted for in the model, genetic effects of the DRD2 and DRD4 polymorphisms were still significant (DRD2 TaqIB: p = 0.001, DRD2 TaqIA: p = 0.008, DRD4 -616 C/G: p = 0.002). Only the DRD4 promoter finding was replicated in the independent sample of psychiatric inpatients (p = 0.007). No association was found with the COMT and DAT1 polymorphisms., Conclusions: Our results of the two independent samples suggest a possible involvement of the DRD4 -616 C/G promoter variant in the development of BPD traits. In addition, an association of the DRD2 genetic polymorphisms with impulsive self-damaging behaviors was also demonstrated.

Gene variants of the serotonin transporter have been associated with vulnerability to affective disorders. In particular, the presence of one or two copies of the short (s) allele of the 5-HTTLPR polymorphism has been associated with reduced serotonin transporter expression and function, and vulnerability to affective disorders. To test for an association between variants of the serotonin transporter gene polymorphism (5-HTTLPR) and relevant clinical features of borderline personality disorder (BPD), a psychiatric disorder with symptoms characteristic for serotonin dysfunction, 77 women with BPD were genotyped in the 5-HTTLPR polymorphism. They rated their subjective experience of borderline-specific, depressive, anxious and obsessive-compulsive symptoms, and were interviewed about lifetime incidence of suicide attempts and self-harming acts. Carriers of two s alleles of the 5-HTTLPR reported more symptoms of borderline, depression, anxiety and obsessive-compulsive behaviours, but not of suicidal and self-injury behaviour, compared to carriers of a long (l) allele. This indicates that the 5-HTTLPR ss homozygous genotype might influence serotonin function affecting susceptibility to both borderline-specific, depressive, anxious and obsessive-compulsive symptoms in BPD, and leading to a more severe symptomatology related to these clinical features. Further, this suggests that 5-HTT gene variants may not be as influential on suicidal and self-injury behaviour in BPD., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

The Iowa Gambling Task (IGT) was used to examine (i) social decision-making in women with borderline personality disorder (BPD), and (ii) the relationship between impaired decision-making and the tryptophan hydroxylase-1 (TPH-1) gene, involved in serotonin synthesis. Forty-two women with BPD and a history of suicide attempts were genotyped, and the frequency of a TPH-1 haplotype previously uniquely associated with BPD was calculated. The BPD group scored significantly lower than a control group in the IGT. Furthermore, the TPH-1 haplotype displayed a significantly higher frequency in BPD participants with impaired decision making, compared to BPD participants with normal scores. These findings suggest that impaired decision-making as determined by the IGT is a feature of BPD and may be (i) associated with serotonin dysfunction, and (ii) possibly relevant for suicidal behavior.

Introduction: Impulsiveness and aggressiveness are characteristics of borderline personality disorder and are associated to a serotoninergic system dysfunction. Serotonin transporter polymorphisms have been linked to aggressive and impulsive behaviors. The short allele (S) in depression is associated to a worse response to selective serotonin reuptake inhibitors (SSRI). This study aims to study these polymorphisms to predict the response of aggressive and impulsive behaviors to SSRIs in borderline personality disorder., Method: Fifty-nine patients with DSM-IV borderline personality disorder in accordance with the International Personality Disorder Examination (IPDE) and without axis 1 disease were treated with flexible doses of fluoxetine for 12 weeks. The patients were evaluated with the Overt Aggression Scale Modified (OAS-M) at the beginning and at 2, 4, 8 and 12 weeks of treatment. Polymorphisms L and S of the serotonin transporter promoter region were determined. Response to fluoxetine of the LL carriers versus the S carriers (LS+SS) was compared., Results: LL carriers had a better response than S carriers in the reduction of total OAS-M scores and on the aggressiveness and irritability components of the OAS-M., Conclusions: L-allele carriers responded better to fluoxetine than S carriers, in a similar way as in depression. The S allele may represent a common factor of bad response to SSRI in diseases associated to serotoninergic system dysfunction.

Borderline personality disorder (BPD) is a chronic, disabling, and high-risk mental disorder characterized by a pervasive pattern of instability in regulation of emotion, interpersonal relationships, self-image, and impulse control beginning in early adulthood. BPD affects about 1%-2% of the general population and has a high mortality rate as a result of suicide and impulsive behaviour. The serotonin 2A receptor gene (HTR2A) is considered a candidate gene for BPD because multiple lines of evidence suggest that it plays an important role in suicide, impulsivity and emotional liability. To test for an association between HTR2A and BPD, we genotyped four polymorphisms, rs6313 (T102C), rs4941573, rs2296972 and rs6314 (His452Tyr), in 111 Caucasian patients with BPD and 287 Caucasian healthy controls. The program UNPHASED was used to compare allele and haplotype frequencies between cases and controls. We did not find a significant association between HTR2A and BPD based on allele, genotype or haplotype analyses. However, there were significant associations between HTR2A and personality traits in the BPD patients. The C allele of rs6313 and the A allele of rs4941573 associated with a higher Extraversion score. Our results suggest that the serotonin 2A receptor gene may not play a major role in the aetiology of borderline personality disorder, but may have a role in personality traits.

Rationale and Objective: Impulsive behavior has been suggested to occur due to a dysfunction of serotonergic 5-HT neurotransmission. After evaluation by a self-reporting measure, a polymorphism in the promoter of the 5-HT2A receptor gene has been proposed to underlie the impulsive behavior; however, this hypothesis is not convincing. In this study, we examined whether this 5-HT2A receptor gene polymorphism is involved in impulsive aggression by evaluating a behavioral task (go/no-go task) in normal volunteers., Materials and Methods: The polymorphism of the 5-HT2A receptor gene promoter was analyzed by polymerase chain reaction using lymphocytes from 71 volunteers. Impulsivity was defined as the number of commission errors (responding when one should not) made during a go/no-go task (a larger number of commission errors indicates greater difficulty in inhibiting the behavior)., Results: The subjects in the group with the A-1438A allele of the 5-HT2A receptor gene (A-1438A group) made more commission errors under the punishment-reward condition in a go/no-go task than those in the G-1438G group., Conclusions: These results suggest the possible involvement of the A-1438A polymorphism of the 5-HT2A receptor gene in impulsive behavior; this was evaluated using a behavioral task measure that can directly reveal the traits of human impulsive behavior.

Background: Borderline personality disorder (BPD) is often co-morbid with major depression and may complicate its treatment. We were interested in differences in genetic and developmental risk factors between depressed patients with or without a co-morbid BPD., Method: Out-patients with major depressive disorder were recruited for two treatment trials. Assessment of depressed patients included the assessment of personality disorders, developmental risk factors and DNA samples for genetic analyses., Results: In each study there was a significant association between the 9-repeat allele of the dopamine transporter (DAT1) and BPD, with odds ratios (OR) > 3 and p < or = 0.02. This association remained significant when developmental risk factors for BPD (childhood abuse and neglect and borderline temperament) were also included in the analyses. The OR was even larger in the depressed patients aged > or = 35 years (OR 9.31, p = 0.005)., Conclusion: This replicated association in depressed patients between the 9-repeat allele of DAT1 and BPD may provide clues to understanding the neurobiology of BPD. The finding that the association is larger in the older depressed patients, suggests that the 9-repeat allele may be associated with a poorer prognosis BPD, rather than a young adult limited variant of BPD.

Objective: To examine whether the T allele of G protein beta3 (GNbeta3) is associated with self-mutilation in depressed patients., Method: A history of self-mutilation was systematically inquired about when recruiting depressed patients for a long-term treatment trial. Risk factors such as borderline personality disorder and childhood abuse experiences were systematically assessed, and patients were genotyped for polymorphisms of GNbeta3., Results: The T allele of GNbeta3, borderline personality disorder and childhood sexual abuse were all significantly associated with self-mutilation in depressed patients. These associations were significant in both univariate and multivariate analyses, and as predicted were stronger in young depressed patients than in depressed patients of all ages., Conclusions: If the association between the T allele of GNbeta3 and self-mutilation can be replicated, this may provide clues to understanding the neurobiology of self-mutilation.