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Early-life adversity (ELA) is characterized by exposure to traumatic events during early periods of life, particularly involving emotional, sexual and/or physical adversities during childhood. Mental disorders are strongly influenced by environmental and lifestyle-related risk factors including ELA. However, the molecular link between ELA and the risk of an adult mental disorder is still not fully understood. Evidence is emerging that long-lasting changes in the epigenetic processes regulating gene expression, such as DNA methylation, play an important role in the biological mechanisms linking ELA and mental disorders. Based on a recent study, we analyzed the DNA methylation of a specific CpG site within the gene PXDN -cg10888111-in blood in the context of ELA across a set of psychiatric disorders, namely Borderline Personality Disorder (BPD), Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD), and its potential contribution to their pathogenesis. We found significant hypermethylation in mentally ill patients with high levels of ELA compared to patients with low levels of ELA, whereas cg10888111 methylation in healthy control individuals was not affected by ELA. Further investigations revealed that this effect was driven by the MDD cohort. Providing a direct comparison of cg10888111 DNA methylation in blood in the context of ELA across three mental disorders, our results indicate the role of PXDN regulation in the response to ELA in the pathogenesis of mental disorders, especially MDD. Further studies will be needed to validate these results and decipher the corresponding biological network that is involved in the transmission of ELA to an adult mental disorder in general.

Creativity and mental disorders are sometimes seen as intertwined, but research is still unclear on whether, how much, and why. Here we explore the potential role of shared genetic factors behind creativity and symptoms of borderline personality disorder (BPD, characterized by mood swings and randomness of thoughts). Data were collected from 6745 twins (2378 complete pairs) by the Netherlands Twin Register on BPD scores (PAI-BOR questionnaire) and working in a creative profession (proxy for creativity). First, we tested whether there is an association between BPD symptoms and creative professions. Results confirmed that individuals scoring higher on the BPD spectrum are more likely to have a creative profession (Cohen's d = 0.16). Next, we modeled how much of this association reflects underlying genetic and/or environmental correlations-by using a bivariate classical twin design. We found that creativity and BPD were each influenced by genetic factors (heritability = 0.45 for BPD and 0.67 for creativity) and that these traits are genetically correlated rG = 0.17. Environmental influences were not correlated. This is evidence for a common genetic mechanism between borderline personality scores and creativity which may reflect causal effects and shed light on mechanisms., (© 2024. The Author(s).)

Loneliness, influenced by genetic and environmental factors such as childhood maltreatment, is one aspect of interpersonal dysfunction in Borderline Personality Disorder (BPD). Numerous studies link loneliness and BPD and twin studies indicate a genetic contribution to this association. The aim of our study was to investigate whether genetic predisposition for loneliness and BPD risk overlap and whether genetic risk for loneliness contributes to higher loneliness reported by BPD patients, using genome-wide genotype data. We assessed the genetic correlation of genome-wide association studies (GWAS) of loneliness and BPD using linkage disequilibrium score regression and tested whether a polygenic score for loneliness (loneliness-PGS) was associated with case-control status in two independent genotyped samples of BPD patients and healthy controls (HC; Witt2017-sample: 998 BPD, 1545 HC; KFO-sample: 187 BPD, 261 HC). In the KFO-sample, we examined associations of loneliness-PGS with reported loneliness, and whether the loneliness-PGS influenced the association between childhood maltreatment and loneliness. We found a genetic correlation between the GWAS of loneliness and BPD in the Witt2017-sample (rg = 0.23, p = 0.015), a positive association of loneliness-PGS with BPD case-control status (Witt2017-sample: NkR² = 2.3%, p = 2.7*10 -12 ; KFO-sample: NkR² = 6.6%, p = 4.4*10 -6 ), and a positive association between loneliness-PGS and loneliness across patient and control groups in the KFO-sample (β = 0.186, p = 0.002). The loneliness-PGS did not moderate the association between childhood maltreatment and loneliness in BPD. Our study is the first to use genome-wide genotype data to show that the genetic factors underlying variation in loneliness in the general population and the risk for BPD overlap. The loneliness-PGS was associated with reported loneliness. Further research is needed to investigate which genetic mechanisms and pathways are involved in this association and whether a genetic predisposition for loneliness contributes to BPD risk., (© 2023. The Author(s).)

Borderline personality disorder (BPD) is a highly prevalent psychiatric disorder and presents a complex therapeutic challenge due to limited treatment modalities. Recent focus has converged on the endocannabinoid system (ECS) as a prospective modulator of psychopathological processes in BPD. To address this hypothesis, we analysed plasma endocannabinoid concentrations, specifically anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in a cohort of 49 female BPD patients and 32 matched healthy controls (HC). Additionally, we examined the effect of the FAAH polymorphism rs324420 and correlates with psychopathology. The results indicate heightened AEA levels and, by trend, augmented 2-AG levels within the patient group, as compared to the HC group. Significant between group differences in AEA levels were evident in the CC genotype ( FAAH_ rs324420) but not in A-allele carriers while the commonly observed difference in AEA levels between A-allele carriers as compared to the CC genotype was not evident in patients. An effect of genotype was found with higher ratings of depression (Beck's depression inventory, BDI-II) in the CC genotype compared to A-allele carriers ( FAAH _rs32442), particularly in the patients. Significant alterations in AEA (and by trend in 2-AG) in patients with BPD may relate to compensatory ECS activity. The finding that the effect is most pronounced in CC homozygotes, might point towards a countermeasure to balance physiologically lower baseline AEA levels. The findings warrant further research to develop potentially beneficial psychopharmacological therapies.

Background: Previous studies have shown that there is a correlation between diseases of the thyroid gland and mental illnesses; however, any causal relationship between them remains unclear. This study aimed to evaluate the causal relationship between borderline personality disorder and four thyroid diseases., Methods: The causal relationship was inferred using double-sample Mendelian randomization analysis of appropriate instrumental variables from genome-wide association studies. We calculated the estimated value of the effect using various statistical methods., Results: Borderline personality disorder was a risk factor for non-toxic single thyroid nodules with each increase in standard deviation increasing the risk of a non-toxic single thyroid nodule by 1.13 times (odds ratio = 1.131; 95% confidence interval, 1.006-1.270; P=0.039). There was no evidence of a correlation between borderline personality disorder and hyperthyroidism/thyrotoxicosis, hypothyroidism, and autoimmune thyroiditis., Conclusion: This study showed that there is a positive causal correlation between borderline personality disorder and non-toxic single thyroid nodules but not with other thyroid diseases. This means that thyroid status should be monitored in patients with borderline personality disorder. However, the possibility of a causal relationship between other mental illnesses and thyroid diseases requires further research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Li, Qi, Yuan and Ding.)

Borderline personality disorder (BPD) is a severe psychiatric condition that affects up to 2.7% of the population and is highly linked to functional impairment and suicide. Despite its severity, there is a lack of knowledge about its pathophysiology. Studies show genetic influence and childhood violence as factors that may contribute to the development of BPD; however, the involvement of neuroinflammation in BPD remains poorly investigated. This article aimed to explore the pathophysiology of BPD according to the levels of brain-derived neurotrophic factor (BDNF), inflammatory cytokines, and oxidative stress substances that exacerbate neuronal damage. Few articles have been published on this theme. They show that patients with BPD have a lower level of BDNF and a higher level of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in peripheral blood, associated with increased plasma levels of oxidative stress markers, such as malondialdehyde and 8-hydroxy-2-deoxyguanosine. Therefore, more research on the topic is needed, mainly with a pre-clinical and clinical focus.

Objectives: Behavioural dysregulation is a heritable core symptom domain in borderline personality disorder (BPD) that is likely influenced by the integrity of executive functions (EFs). However, the extent to which familial risk for BPD confers decrement to EFs has yet to be comprehensively studied., Methods: In this family study, probands with BPD ( n  = 73), first-degree biological relatives ( n  = 65), and healthy controls without psychiatric diagnoses ( n  = 77) were assessed in abstraction, attentional vigilance, working memory, cognitive flexibility, interference resolution, planning, problem solving, and response inhibition., Results: In univariate analyses, probands demonstrated lower response inhibition than relatives. Comparatively, discriminant function analyses revealed that lower interference resolution and response inhibition jointly discriminated probands from relatives and controls, whereas a combination of less efficient problem solving and difficulty manipulating mental information discriminated probands and relatives from controls. Moreover, the subset of psychiatrically non-affected relatives demonstrated a pattern of resilience to psychiatric morbidity substantiated by stronger response inhibition and abstraction abilities despite less efficient problem solving., Conclusions: Familial risk for BPD is represented predominantly by a pattern of problem-solving and working memory deficits. Resilience to a psychiatric disorder in non-affected relatives reflects both EF weaknesses and strengths, highlighting potential protective factors that should be considered in future neurocognitive research on BPD families.

Both environmental (e.g. interpersonal traumatization during childhood and adolescence) and genetic factors may contribute to the development of Borderline Personality Disorder (BPD). Twin studies assessing borderline personality symptoms/features in the general population indicate that genetic factors underlying these symptoms/features are shared in part with the personality traits of the Five Factor Model (FFM) of personality-the "Big Five". In the present study, the genetic overlap of BPD with the Big Five -Openness to Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism- was assessed. Linkage disequilibrium score regression was used to calculate genetic correlations between a genome-wide association study (GWAS) in central European populations on BPD (N = 2543) and GWAS on the Big Five (N = 76,551-122,886, Neuroticism N = 390,278). Polygenic scores (PGS) were calculated to test the association of the genetic disposition for the personality traits with BPD case-control status. Significant positive genetic correlations of BPD were found with Neuroticism (rg = 0.34, p = 6.3*10 -5 ) and Openness (rg = 0.24, p = 0.036), but not with the other personality traits (all | rg | <0.14, all p > 0.30). A cluster and item-level analysis showed positive genetic correlations of BPD with the Neuroticism clusters "Depressed Affect" and "Worry", and with a broad range of Neuroticism items (N = 348,219-376,352). PGS analyses confirmed the genetic correlations, and found an independent contribution of the personality traits to BPD risk. The observed associations indicate a partially shared genetic background of BPD and the personality traits Neuroticism and Openness. Larger GWAS of BPD and the "Big Five" are needed to further explore the role of personality traits in the etiology of BPD., (© 2022. The Author(s).)

Understanding of the biological factors that run in families affected with borderline personality disorder (BPD) is limited. The authors investigated the familial aggregation of neurophysiological biomarkers of response inhibition in the first-degree biological relatives of probands with BPD and associations with psychiatric diagnosis and impulsive traits. In the present study, psychiatric diagnoses and impulsive traits were measured in BPD probands (n = 86), psychiatrically affected and non-affected relatives (n = 60) and controls (n = 83). While undergoing neuroimaging using functional near-infrared spectroscopy, prefrontal cortex (PFC) activation was measured during a go/no-go response inhibition task and compared between probands, relatives and controls. Additionally, non-psychiatrically affected relatives and controls were contrasted to examine the potential impact of familial risk for BPD on response inhibition-related PFC activation in the absence of confounding psychiatric morbidity. Probands showed bilateral decreases in PFC activation during response inhibition compared to relatives and controls. Conversely, both affected and non-affected relatives displayed higher activation than controls and probands in left lateral/medial and right medial PFC, although non-affected relatives showed a lesser extent of activation than affected relatives. Probands and controls reporting greater impulsive traits displayed deactivation across the PFC during response inhibition, whereas relatives showed increased activation. In this first family study of neuroimaging biomarkers in BPD, we show that the familial risk for BPD is reflected in activation of the PFC during response inhibition, with lifetime psychiatric diagnosis and higher impulsive traits in relatives associated with larger increases in PFC activity. Higher PFC activity during response inhibition including among non-affected relatives could reflect a neurophysiological compensatory mechanism., (Copyright © 2020 Elsevier Inc. All rights reserved.)

There is a need to identify the subset of individuals with borderline personality disorder (BPD) symptoms at greatest risk for transitioning from suicidal ideation to a suicide attempt. Contemporary models of suicide risk propose that the capability for suicide is necessary for moving from suicidal ideation to a suicide attempt. Few studies have examined dispositional capability factors for suicide, especially among individuals with BPD symptoms. One candidate may be the catechol-o-methyltransferase (COMT) Val 158 Met polymorphism given its influence on pain sensitivity and fear. This study examined the interactive relation of BPD symptoms and the COMT Val 158 Met polymorphism to suicidal ideation and suicide attempts. Fifty-nine treatment-seeking patients were recruited. Participants were administered a series of clinical interviews to evaluate BPD symptoms and suicidal thoughts and behaviors. Saliva samples were collected for genotyping. The relation between BPD symptoms and suicidal ideation was not influenced by the Val 158 Met polymorphism. However, among Val/Val carriers, the probability of a lifetime suicide attempt increased as BPD symptom severity increased. Findings provide preliminary support for the Val/Val variant as a dispositional factor that may increase risk for suicide attempts in BPD; however, results must be interpreted with caution until replication of findings occurs in larger samples., (Copyright © 2021. Published by Elsevier B.V.)

Background: Borderline Personality Disorder (BPD) is a psychiatric disorder associated with significant morbidity and mortality. However, the neurobiological alterations underlying the condition remain poorly understood. As a result, existing treatments remain inadequate. One of the main risk factors for the development of BPD is a history of childhood maltreatment. However, it is considered neither causative nor specific to the condition. Current theory is therefore increasingly moving toward a 'Gene x Environment' (GxE) model of the condition. The purpose of the current work was to conduct a systematic literature review, which comprehensively identifies all published molecular level GxE studies that have explored the role of specific genetic loci, in influencing the risk of BPD following exposure to childhood abuse or neglect., Methods: Four electronic databases were used to systematically search for molecular level GxE studies of any design, which focused on the development of BPD following exposure to childhood abuse or neglect, without language or date restrictions. Articles were screened independently by two reviewers and results were synthesized narratively., Results: A total of 473 articles were screened of which sixteen were selected for inclusion in our review. Implicated genes were categorised according to their influence on; Neurotransmitter Systems, Neurodevelopment and Neuroendocrine Systems., Conclusions: The identified studies have produced several relevant and statistically significant results. Of particular note, is the repeated finding that genes involved in HPA axis regulation, may be altered by exposure to childhood maltreatment, influencing subsequent susceptibility to BPD. This is both biologically plausible and of potential clinical significance., (Copyright © 2020. Published by Elsevier Ltd.)

The purpose of this study is to examine whether theory of mind (ToM) is an endophenotypic marker of borderline personality disorder (BPD), thus constituting an etiopathogenic factor of the disease. This would suggest familial vulnerability to BPD. This was a case-control study involving 146 individuals with 57 BPD patients, 32 first-degree relatives, and 57 controls (median age of BPD and control = 33.4 years; relatives = 52.9 years; BPD females and controls = 91.2%; female relatives = 62.5%). All the participants completed the Spanish version of the Movie for the Assessment of Social Cognition test to evaluate the ToM subclassification: interpretation of emotions, thoughts and intentions. BPD patients and their healthy first-degree relatives exhibited significant deficits in the correct interpretation of emotions and intentions compared to healthy controls. Both patients with BPD and their healthy first-degree relatives exhibited significant deficits in ToM, which suggests that it may be an etiopathogenic factor of BPD, and ToM (interpretation of emotions, thoughts and intentions) is a possible endophenotypic marker of BPD, suggesting a genetic predisposition to the disorder. Therefore, ToM could be considered as an indicator for the early detection of the disorder of and intervention for BPD.

Previous research suggests that childhood maltreatment is associated with epigenetic modification of genes involved in hypothalamic-pituitary-adrenal (HPA) functioning, which could cause dysregulation of the stress response system. If pervasive, this may be associated with the development of stress-related disorder in adults, including affective disorders, anxiety disorders, post-traumatic stress disorder (PTSD) or borderline-personality disorder (BPD). The majority of studies have focused on DNA methylation of the glucocorticoid receptor gene (NR3C1) and the FKBP5 encoding gene, which regulates the sensitivity of the glucocorticoid receptor (GR). How methylation of NR3C1 and FKBP5 interferes with childhood adversity and psychopathology as well as empathy is an under-researched issue. Here, we sought to investigate the association of childhood maltreatment in a sample of 89 individuals (44 healthy participants and 45 patients diagnosed with BPD) with the methylation of the 1F promoter region of NR3C1 and the intron 7 of FKBP5 as well as with different measures of psychopathology and empathy. Methylation of FKBP5 (bin 2) correlated with anxiety (SCL-90-R) and the global psychopathological symptom load index (GSI), as well as with lower empathic perspective-taking abilities. Psychopathology and empathy impairments correlated with the level of childhood maltreatment. No difference in FKBP5 methylation was observed between the clinical and the non-clinical group. Methylation of NR3C1 was lower in BPD patients compared to controls, yet with small differences. The results are discussed regarding their biological relevance, including possible evolutionary explanations. In short, the regulation of the GR sensitivity by methylation of FKBP5 correlated with psychopathology and empathy scores, while no correlation emerged with the severity of childhood adversity., Competing Interests: The authors have declared that no competing interests exist.

Family and twin studies of Borderline Personality Disorder (BPD) have found familial aggregation and genetic propensity for BPD, but estimates vary widely. Large-scale family studies of clinically diagnosed BPD are lacking. Therefore, we performed a total-population study estimating the familial aggregation and heritability of clinically diagnosed BPD. We followed 1,851,755 individuals born 1973-1993 in linked Swedish national registries. BPD-diagnosis was ascertained between 1997 and 2013, 11,665 received a BPD-diagnosis. We identified relatives and estimated sex and birth year adjusted hazard ratios, i.e., the rate of BPD-diagnoses in relatives to individuals with BPD-diagnosis compared to individuals with unaffected relatives, and used structural equation modeling to estimate heritability. The familial association decreased along with genetic relatedness. The hazard ratio was 11.5 (95% confidence interval (CI) = 1.6-83.8) for monozygotic twins; 7.4 (95% CI = 1.0-55.3) for dizygotic twins; 4.7 (95% CI = 3.9-5.6) for full siblings; 2.1 (95% CI = 1.5-3.0) for maternal half-siblings; 1.3 (95% CI = 0.9-2.1) for paternal half-siblings; 1.7 (95% CI = 1.4-2.0) for cousins whose parents were full siblings; 1.1 (95% CI = 0.7-1.8) for cousins whose parents were maternal half-siblings; and 1.9 (95% CI = 1.2-2.9) for cousins whose parents were paternal half-siblings. Heritability was estimated at 46% (95% CI = 39-53), and the remaining variance was explained by individually unique environmental factors. Our findings pave the way for further research into specific genetic variants, unique environmental factors implicated, and their interplay in risk for BPD.

Borderline personality disorder (BPD) is a severe and highly prevalent psychiatric disorder, more common in females than in males and with notable differences in presentation between genders. Recent studies have shown that epigenetic modifications such as DNA methylation may modulate gene × environment interactions and impact on neurodevelopment. We conducted an epigenome wide study (Illumina Infinium HumanMethylation450k beadchip) in a group of BPD patients with (N = 49) and without (N = 47) childhood traumas and in a control group (N = 44). Results were confirmed in a replication cohort (N = 293 BPD patients and N = 114 controls) using EpiTYPER assays. Differentially methylated CpG sites were observed in several genes and intragenic regions in the X chromosome (PQBP1, ZNF41, RPL10, cg07810091 and cg24395855) and in chromosome 6 (TAP2). BPD patients showed significantly lower methylation levels in these CpG sites than healthy controls. These differences seemed to be increased by the existence of childhood trauma. Comparisons between BPD patients with childhood trauma and patients and controls without revealed significant differences in four genes (POU5F1, GGT6, TNFRSF13C and FAM113B), none of them in the X chromosome. Gene set enrichment analyses revealed that epigenetic alterations were more frequently found in genes controlling oestrogen regulation, neurogenesis and cell differentiation. These results suggest that epigenetic alterations in the X chromosome and oestrogen-regulation genes may contribute to the development of BPD and explain the differences in presentation between genders. Furthermore, childhood trauma events may modulate the magnitude of the epigenetic alterations contributing to BPD.

Large-scale family studies on the co-occurrence of attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) are lacking. Thus, we aimed to estimate the co-occurrence and familial co-aggregation of clinically ascertained ADHD and BPD diagnoses using the entire Swedish population. In a register-based cohort design we included individuals born in Sweden 1979-2001, and identified their diagnoses during 1997-2013; in total, 2,113,902 individuals were included in the analyses. We obtained clinical diagnoses of ADHD and BPD from inpatient and outpatient care. Individuals with an ADHD diagnosis had an adjusted (for birth year, sex, and birth order) odds ratio (aOR) of 19.4 (95% confidence interval [95% CI] = 18.6-20.4) of also having a BPD diagnosis, compared to individuals not diagnosed with ADHD. Having a sibling with ADHD also increased the risk for BPD (monozygotic twins, aOR = 11.2, 95% CI = 3.0-42.2; full siblings, aOR = 2.8, 95% CI = 2.6-3.1; maternal half-siblings, aOR = 1.4, 95% CI = 1.2-1.7; paternal half-siblings, aOR = 1.5, 95% CI = 1.3-1.7). Cousins also had an increased risk. The strength of the association between ADHD and BPD was similar in females and males, and full siblings showed similar increased risks regardless of sex. Among both males and females, ADHD and BPD co-occur within individuals and co-aggregate in relatives; the pattern suggests shared genetic factors and no robust evidence for etiologic sex differences was found. Clinicians should be aware of increased risks for BPD in individuals with ADHD and their relatives, and vice versa.

Objective: Borderline personality disorder in adolescence remains a controversial construct. We addressed concerns about the prognostic significance of adolescent borderline pathology by testing whether borderline symptoms at age 12 years predict functioning during the transition to adulthood, at age 18 years, in areas critical to life-course development., Method: We studied members of the Environmental Risk (E-Risk) Longitudinal Twin Study, which tracks the development of a birth cohort of 2,232 British twin children. At age 12, study members' borderline symptoms were measured using mothers' reports. At age 18, study members' personality, psychopathology, functional outcomes, and experiences of victimization were measured using self-reports, coinformant reports, and official records., Results: At age 18, study members who had more borderline symptoms at age 12 were more likely to have difficult personalities, to struggle with poor mental health, to experience poor functional outcomes, and to have become victims of violence. Reports of poor outcomes were corroborated by coinformants and official records. Borderline symptoms in study members at 12 years old predicted poor outcomes over and above other behavioral and emotional problems during adolescence. Twin analyses showed that borderline symptoms in 12-year-olds were influenced by familial risk, particularly genetic risk, which accounted for associations with most poor outcomes at age 18., Conclusion: Borderline symptoms in 12-year-olds signal risk for pervasive poor functioning during the transition to adulthood. This association is driven by genetic influences, suggesting that borderline symptoms and poor outcomes are manifestations of shared genetic risk., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Loneliness is related to mental and somatic health outcomes, including borderline personality disorder. Here, we analyze the sources of variation that are responsible for the relationship between borderline personality features (including four dimensions, affective instability, identity disturbance, negative relationships, self-harm and a total score) and loneliness. Using genetically informative data from two large nonclinical samples of adult twin pairs from Australia and the Netherlands (N = 11,329), we estimate the phenotypic, genetic and environmental correlations between self-reported borderline personality features and loneliness. Individual differences in borderline personality and loneliness were best explained by additive genetic factors with heritability estimates h2 = 41% for the borderline personality total score and h2 = 36% for loneliness, with the remaining variation explained by environmental influences that were not shared by twins from the same pair. Genetic and environmental factors influencing borderline personality (total score and four subscales separately) were also partial causes of loneliness. The correlation between loneliness and the borderline personality total score was rph = .51. The genetic correlation was estimated at rg = .64 and the environmental correlation at re = .40. Our study suggests common etiological factors in loneliness and borderline personality features.

Background: Borderline personality disorder (BPD) is caused by a variety of biological and environmental factors. Accumulating evidence suggests that childhood maltreatment is a risk environmental factor in the development of BPD, but research on the genetic pathology of BPD is still in its early stages, and very little is known about the oxytocin receptor (OXTR) gene. The purpose of this study is to further explore the interactive effects between OXTR gene polymorphisms and childhood maltreatment on BPD risk., Methods: Among the 1804 Chinese Han male inmates, 765 inmates who had BPD or antisocial personality disorder (ASPD) or highly impulsive or violent crime were considered as high-risk inmates and included in this study. Childhood maltreatment, BPD, antisocial personality disorder (ASPD) and impulsivity were measured by self-reported questionnaires. Peripheral venous blood was collected for the genotype test., Results: Analyses revealed that the BP group (inmates with BPD features) had higher rs53576 AA genotype frequency and rs237987 AA genotype frequency than the non-BP group, while the statistical significances were lost after Bonferroni correction. Total childhood maltreatment score, emotional abuse and neglect could positively predict BPD risk. Among the high-risk samples, rs53576 GG genotype carriers had higher BPD scores at higher levels of physical abuse and sexual abuse and had lower BPD scores at lower levels of physical abuse and sexual abuse., Conclusions: The findings suggest that the interaction between OXTR gene variations and childhood maltreatment is an important mechanism for the development of BPD. The moderating role of the OXTR gene provides evidence for gene plasticity.

Background: Parental characteristics and practices predict borderline personality disorder (BPD) symptoms in children. However, it is difficult to disentangle whether these effects are genetically or environmentally mediated. The present study examines the contributions of genetic and environmental influences by comparing the effects of familial risk factors (i.e. parental psychopathology and borderline traits, maladaptive parenting, marital discord) on child BPD traits in genetically related (biological) and non-related (adoptive) families., Methods: Data are from 409 adoptive and 208 biological families who participated in the Siblings Interaction and Behavior Study (SIBS) and 580 twin families the Minnesota Twin Family Study (MTFS). Parent characteristics and practices included parental psychopathology (measured via structured clinical interviews), parental BPD traits, parenting behaviors, and marital discord. A series of multi-level regression models were estimated to examine the relationship of familial risk factors to child BPD traits and to test whether children's adoptive status moderated the association., Results: Symptom counts of parents' conduct disorder, adult antisocial behavior, nicotine, alcohol, and illicit drug dependence, and paternal BPD traits substantially predicted child BPD traits only in biological offspring, implying genetic transmission. Maternal BPD traits and both maternal and paternal conflict, lack of regard, and lack of involvement predicted offspring BPD traits regardless of the adoptive status, implying environmental transmission., Conclusions: Parental externalizing psychopathology and father's BPD traits contribute genetic risk for offspring BPD traits, but mothers' BPD traits and parents' poor parenting constitute environmental risks for the development of these offspring traits.

Facial emotion recognition (FER) has been described to be impaired in borderline personality disorder (BPD), especially for neutral faces. Genetic modulation of FER has been studied in healthy individuals and some psychiatric conditions, but no genetic association studies have been conducted in BPD hitherto. The main objective of our study was to explore the influence of the serotonin-transporter-linked promoter region (5HTTLPR) and catechol-o-methyltransferase (COMT) Val158Met on facial emotion processing among BPD patients. To that end, seventy-six BPD outpatients were asked to complete a computer-based facial affect recognition task, representing four emotions (neutral, happy, fearful or angry). Accuracy of FER and perceptual biases were calculated. The 5HTTLPR and COMT Val158Met polymorphisms were genotyped using saliva samples. Individuals with the high-activity serotonin-transporter genotype and those with the low-activity COMT genotype had significantly more difficulties identifying neutral faces; the former showed stronger bias to perceive neutral faces as happy, and the latter, neutral faces as fearful. Interestingly, the perceptual biases observed in our patients are similar to previous reports in healthy individuals. The authors propose that the ability to accurately recognize neutral faces might be a possible endophenotype of BPD. Sex-genotype interactions were also observed in relation to angry faces and 5HTTLPR, and neutral faces and COMT Val158Met polymorphisms, in line with sex-related differences previously described for both polymorphisms in relation to FER and other cognitive and behavioral outcomes. The impact of inaccurate FER on psychosocial functioning and potential interventions are also discussed., Competing Interests: Declaration of Competing Interest None, (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Genetic factors underlying different personality traits are not entirely understood, particularly how genes interact to modulate their effect. We studied 76 patients diagnosed with borderline personality disorder (BPD), characterized by extreme levels of personality traits, especially neuroticism (N), in which we genotyped two polymorphisms, the 5HTTLPR of the Serotonin transporter (SERT) gene, and the Val66Met of the Brain-derived neurotrophic factor (BDNF) gene., Results: We found an association with SERT, where S-allele carriers had significantly higher levels of N than L-homozygous. Furthermore, we found that the protective effect of L-homozygosity is only evident on A-allele carriers of the BDNF Val66Met polymorphism. Genetic constitution in SERT and BDNF seems to be important in neuroticism, the most relevant personality trait on BPD.

Previous research has suggested that the short (S)-allele of the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) may confer "differential susceptibility" to environmental impact with regard to the expression of personality traits, depressivity and impulsivity. However, little is known about the role of 5-HTTLPR concerning the association between childhood adversity and empathy. Here, we analyzed samples of 137 healthy participants and 142 individuals diagnosed with borderline personality disorder (BPD) focusing on the 5-HTTLPR genotype (S/L-carrier) and A/G SNP (rs25531), in relation to childhood maltreatment and empathy traits. Whereas no between-group difference in 5-HTTLPR genotype distribution emerged, the S-allele selectively moderated the impact of childhood maltreatment on empathic perspective taking, whereby low scores in childhood trauma were associated with superior perspective taking. In contrast, L-homozygotes seemed to be largely unresponsive to variation in environmental conditions in relation to empathy, suggesting that the S-allele confers "differential susceptibility". Moreover, a moderation analysis and tests for differential susceptibility yielded similar results when transcriptional activity of the serotonin transporter gene was taken into account. In conclusion, our findings suggest that the S-allele of the 5-HTTLPR is responsive to early developmental contingencies for "better and worse", i.e. conferring genetic plasticity, especially with regard to processes involving emotional resonance., Competing Interests: The authors have declared that no competing interests exist.

Differential DNA methylation in peripheral tissues has been associated with Borderline Personality Disorder (BPD). Alterations have been found in several genes, among them the Catechol-O-methyltransferase (COMT) gene. COMT is a known neuropsychiatric candidate gene, which contains a genotype variant (Val 108/158 Met) that affects protein function and has been found associated with several psychiatric disorders. In addition, this variant also affects COMT DNA methylation. However, in previous epigenetic studies, the DNA methylation results have not always been controlled for genotype, even though overrepresentation of the Met allele has been frequently reported in cohorts of BPD patients. Therefore, in the present study, we investigated whether alteration of COMT DNA methylation in BPD patients is indeed associated with mental health status or merely influenced by a differential distribution of the COMT genotype between BPD patients and healthy control individuals. We found significant group differences, as well as a strong effect of genotype on COMT DNA methylation. While the direction of effect was different compared to a previous study, our study supports the finding of altered COMT DNA methylation in patients with BPD and reinforces the need to include genotype information in future DNA methylation studies of COMT., (Copyright © 2019 Elsevier B.V. and ECNP. All rights reserved.)

Purpose: To evaluate and understand the genetic and epigenetic basis of bulimia nervosa/bulimia spectrum disorder and comorbid borderline personality disorder (BN/BSD-BPD)., Methods: The present systematic review was conducted in accordance to PRISMA guidelines. Advanced systematic searches of Medline, EMBASE, PsychINFO, Web of Science, Scopus, CINHAL plus, and the Cochrane Library were conducted using the search terms 'bulimia nervosa', 'bulimia spectrum disorder', 'borderline personality disorder', 'genes', and 'genetics'. The search strategy garnered seven studies for inclusion in the present review., Results: Women with BN/BSD-BPD had significantly lower serotonin and monoamine oxidise activity compared to women with BN/BSD or healthy controls (HC). As well, women with BN/BSD-BPD displayed elevated methylation of the dopamine receptor gene promoter, brain-derived neurotrophic factor, and changes in the methylation of the glucocorticoid receptor gene promoter (NR3C1) compared to women with BN/BSD and HC. The results also demonstrated that rates of childhood sexual abuse and childhood physical abuse are higher in those with BN/BSD-BPD than those with BN/BSD and HC, and that these types of abuse are often correlated with the methylation differences seen in BN/BSD-BPD women., Conclusion: Due to the differences observed between individuals with BN/BSD-BPD and those with BN/BSD and HC a genetic/epigenetic aetiological model of BN/BSD-BPD was developed and is proposed in this review. This evidence-based model visually illustrates the current state of the field and draws attention to the need for subsequent research.

Background: Borderline personality disorder (BPD) is characterized by a heterogeneous clinical phenotype that emerges from interactions among genetic, biological, neurodevelopmental, and psychosocial factors. In the present family study, we evaluated the familial aggregation of key clinical, personality, and neurodevelopmental phenotypes in probands with BPD (n = 103), first-degree biological relatives (n = 74; 43% without a history of psychiatric disorder), and non-psychiatric controls (n = 99)., Methods: Participants were assessed on DSM-IV psychiatric diagnoses, symptom dimensions of emotion dysregulation and impulsivity, 'big five' personality traits, and neurodevelopmental characteristics, as part of a larger family study on neurocognitive, biological, and genetic markers in BPD., Results: The most common psychiatric diagnoses in probands and relatives were major depression, substance use disorders, post-traumatic stress disorder, anxiety disorders, and avoidant personality disorder. There was evidence of familial aggregation for specific dimensions of impulsivity and emotion dysregulation, and the big five traits neuroticism and conscientiousness. Both probands and relatives reported an elevated neurodevelopmental history of attentional and behavioral difficulties., Conclusions: These results support the validity of negative affectivity- and impulse-spectrum phenotypes associated with BPD and its familial risk. Further research is needed to investigate the aggregation of neurocognitive, neural and genetic factors in families with BPD and their associations with core phenotypes underlying the disorder.

Background: Borderline personality disorder (BPD) is a pervasive psychiatric disorder characterized by emotion dysregulation, impulsivity, impaired self-perceptions, and interpersonal relationships and currently affects 1-3% of the US population as reported by Torgersen et al. (Arch Gen Psychiatry 58:590-596, Torgersen et al. 2001), Lenzenweger et al. (Biol Psychiatry 62:553-564, Lenzenweger et al. 2007), and Tomko et al. (J Personal Disord 28:734-750, Tomko et al. 2014). One major obstacle to our understanding of the neural underpinnings of BPD is a lack of valid animal models that translate the key known features of the disorder to a system that is amenable to study., Objective: To summarize the etiology, major symptoms, and symptom triggers of BPD and then propose a blueprint for building an animal model of BPD by choosing key components of the disorder that can be implemented in rodents., Results: We identify the role of early life stress and subsequent mild stress in adulthood as contributing etiological factors and the potential use of altered communication between frontal cortices and the amygdala in extinction and habituation, increased impulsivity, dysregulation of the hypothalamic pituitary axis (HPA), and increased neuroinflammation as biological markers of BPD. Building upon these features of BPD, we propose a two-hit animal model that uses maternal abandonment to alter maturation of the HPA axis and mild secondary adult stress to evoke behavioral symptoms such as increased impulsivity and impaired extinction, habituation, and social interactions., Conclusion: Through exploration of the etiology, symptom presentation, and altered neurological function, we propose an animal model of BPD. We believe that a number of existing animal paradigms that model other mental health disorders should be combined in a unique way to reflect the etiology, symptom presentation, and altered neurological function that is evident in BPD. These model, when compared with available human data, will inform research and treatment in humans for better understanding of systems from the micro-molecular level to more global physiology underlying BPD.

Background: Genes associated with the physiological response to stress in the hypothalamic-pituitary-adrenal axis are considered as good candidates for genetic research in borderline personality disorder (BPD)., Methods: In this study, five FKBP5 (a co-chaperone of the glucocorticoid receptor) SNPs (rs3800373, rs9296158, rs737054, rs1360780, rs9470080) were genotyped in a sample of 101 unrelated Caucasian patients with BPD and 111 ethnically matched healthy controls. The interaction between FKBP5 polymorphisms and childhood trauma was also tested., Results: All FKBP5 polymorphisms genotyped showed significant associations with BPD. A main effect of rs9470080 (p = 0.01) and gene x environment (physical abuse) interaction (p = 0.01) was found. A gene x environment (emotional abuse) interaction was also found for rs3800373 (p = 0.03). However, these interactions did not remain significant after multiple testing corrections., Limitations: In this study, only 5 genetic variants were tested and thus tagging of the FKBP5 gene was incomplete. Moreover, the sample size is moderate., Conclusion: BPD is associated with FKBP5 polymorphisms and several types of childhood abuse may modulate the effect between FKBP5 SNPs and this disorder., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Borderline personality disorder (BPD) is fundamentally a syndrome composed of symptoms (primarily of emotional dysregulation) and a number of true personality traits (such as inordinate anger, impulsivity, and a tendency to stress-related paranoid ideation). Whereas schizotypal personality disorder, with its cognitive peculiarities (ideas of reference, odd beliefs, eccentric speech), is closely linked as a genetic condition-"borderline" to the major condition schizophrenia-BPD is less closely linked to bipolar disorder. Some cases of BPD are linked genetically to and are in the "border" of bipolar disorder. But the condition can also arise from adverse post-natal factors: parental cruelty or neglect, or incest. In some BPD patients, both are present: risk genes for bipolar disorder and adverse conditions within the family. The genetic risk is often overlooked. To avoid this, initial evaluations should always include a careful and extensive family history for mood disorders, and should extend out to grandparents, aunts, uncles, and cousins. Where the history suggests a genetic link to bipolar disorder, a mood stabilizer such as lithium or lamotrigine, even in modest doses, may be particularly beneficial, more so than conventional antidepressants. In some patients, ADHD was present in childhood, BPD was diagnosed during or after puberty, and a form of bipolar disorder becomes apparent during their 20s. As for the psychotherapeutic component, the patient's cognitive style and capacity for introspection will help determine whether a primarily expressive (psychoanalytically oriented) technique is preferable or a primarily cognitive-behavioral technique. Flexibility is necessary, since during emotional crises, supportive and limit-setting interventions will be needed, along with psychotropic medications, and where necessary, programs to help combat substance abuse (which is common among patients with BPD).

Background: Studying the phenotypic manifestations of increased genetic liability for Bipolar Disorder (BD) can increase understanding of this disorder., Aims: We assessed whether genetic risk for BD was associated with childhood psychopathology and features of hypomania in young adulthood within a large population-based birth cohort., Methods: We used data from the second Psychiatric Genetics Consortium Genome Wide Association Study (GWAS) for Bipolar Disorder to construct a polygenic risk score (PRS) for each individual in the Avon Longitudinal Study of Parents and Children (ALSPAC). Linear and logistic regression models were used to assess associations between the BD-PRS and emotional/behavioural difficulties, attention deficit hyperactivity disorder (ADHD) and borderline personality disorder (BPD) traits in childhood, as well as hypomania in early adulthood (sample sizes from 2654 to 6111)., Results: The BD-PRS was not associated with total hypomania score, but was weakly associated with a binary measure of hypomania (OR = 1.13, 95%CI 0.98,1.32; p = 0.097), and particularly at higher hypomania symptom thresholds (strongest evidence OR = 1.33, 95%CI 1.07, 1.65; p = 0.01). The BD-PRS was also associated with ADHD (OR = 1.31, 95%CI 1.10, 1.57; p = 0.018), but not with other childhood psychopathology., Limitations: The PRS only captures common genetic variation and currently explains a relatively small proportion of the variance for BD., Conclusions: The BD-PRS was associated with ADHD in childhood, and weakly with adult hypomania, but not with other psychopathology examined. Our findings suggest that genetic risk for BD does not appear to manifest in childhood to the same extent as schizophrenia genetic risk has been reported to do., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

This article reviews the most salient neurobiological information available about borderline personality disorder (BPD) and presents a theoretic model for what lies at the heart of BPD that is grounded in those findings. It reviews the heritability, genetics, and the biological models of BPD, including the neurobiology of affective instability, impaired interoception, oxytocin and opiate models of poor attachment or interpersonal dysfunction, and structural brain imaging over the course of development in BPD; and posits that the core characteristic of BPD may be an impairment in emotional interoception or alexithymia., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Evolutionary models of psychopathology can shed light on gene-environment interactions. Differential susceptibility to the environment means that heritable traits can have positive or negative effects, depending on environmental context. Thus, traits that increase risk for mental disorders when the environment is negative can be adaptive when the environment is positive. This model can be applied to borderline personality disorder, with predictors such as emotional dysregulation and impulsivity seen as temperamental variations leading to negative effects in an unfavorable environment but to positive effects in a favorable environment. This model may also be useful in conceptualizing the mechanisms of effective therapy for borderline personality disorder.

Background: The importance of epigenetic alterations in psychiatric disorders is increasingly acknowledged and the use of DNA methylation patterns as markers of disease is a topic of ongoing investigation. Recent studies suggest that patients suffering from Borderline Personality Disorder (BPD) display differential DNA methylation of various genes relevant for neuropsychiatric conditions. For example, several studies report differential methylation in the promoter region of the brain-derived neurotrophic factor gene (BDNF) in blood. However, little is known about BDNF methylation in other tissues., Results: In the present study, we analyzed DNA methylation of the BDNF IV promoter in saliva and blood of 41 BPD patients and 41 matched healthy controls and found significant hypermethylation in the BPD patient's saliva, but not blood. Further, we report that BDNF methylation in saliva of BPD patients significantly decreased after a 12-week psychotherapeutic intervention., Conclusions: Providing a direct comparison of BDNF methylation in blood and saliva of the same individuals, our results demonstrate the importance of choice of tissue for the study of DNA methylation. In addition, they indicate a better suitability of saliva for the study of differential BDNF methylation in BPD patients. Further, our data appear to indicate a reversal of disease-specific alterations in BDNF methylation in response to psychotherapy, though further experiments are necessary to validate these results and determine the specificity of the effect.

Purpose of Review: We review the existing literature on gene-environment interactions (G×E) and epigenetic changes primarily in borderline personality disorder (BPD) but also in antisocial, schizotypal, and avoidant personality disorders., Recent Findings: Research supports that susceptibility genes to BPD or its underlying traits may be expressed under certain environmental conditions such as physical or childhood sexual abuse. Epigenetic modifications of neurodevelopment- and stress-related genes are suggested to underlie the relationship between early life adversary and borderline personality disorder. Only limited studies have investigated the role of gene-environment interactions and epigenetic changes in the genesis of antisocial, schizotypal, and avoidant personality disorders. Considering the lack of pharmacological treatment for most personality disorders, the emerging evidence on the critical role of G×E and epigenetic changes in the genesis of personality disorders could help develop more biologically oriented therapeutic approaches. Future studies should explore the potential of this new therapeutic dimension.

Background: Parental major depressive disorder (MDD) and borderline personality disorder (BPD) are associated with increased risk of offspring psychopathology. It is unclear whether BPD in depressed parents infers greater risk than depression alone. We hypothesized that BPD features in depressed parents would be associated with higher morbid risk of offspring MDD and substance use disorders (SUDs)., Methods: Participants included 912 psychiatric outpatients with a principal diagnosis of MDD. Semi-structured interviews determined diagnoses of parents and their 2,011 reported offspring. We compared the offspring's morbid risk of MDD and SUDs based on whether their parents had BPD, ≥1 BPD criteria, and by each criterion., Results: Offspring of parents with ≥1 BPD criteria had higher morbid risk of MDD and SUDs. Differences were insignificant when comparing by BPD diagnosis. Anger and impulsivity were associated with increased risk of MDD, and emptiness was associated with increased risk of SUDs., Conclusions: Results suggest that BPD features confer additional risk to offspring beyond that of parental depression alone. Parental anger and impulsivity may be particularly important in determining risk of MDD, and parental feelings of emptiness may be particularly important for risk of SUDs. Limitations, future directions, and treatment implications are discussed.

Background and Aims: Individual differences in DSM-IV personality disorders (PDs) are associated with increased prevalence of substance use disorders. Our aims were to determine which combination of PDs trait scores best predict cannabis use (CU) and cannabis use disorder (CUD), and to estimate the size and significance of genetic and environmental risks in PD traits shared with CU and CUD., Design: Linear mixed-effects models were used to identify PD traits for inclusion in twin analyses to explore the genetic and environmental associations between the traits and cannabis use., Setting: Cross-sectional data were obtained from Norwegian adult twins in a face-to-face interview in 1999-2004 as part of a population-based study of mental health., Participants: Subjects were 1419 twins (μ age  = 28.2 years, range = 19-36) from the Norwegian Institute of Public Health Twin Panel with complete PD and cannabis data., Measurements: PD traits were assessed using DSM-IV criteria. Life-time CU and CUD were based on DSM-IV abuse and dependence criteria, including withdrawal and craving., Findings: After adjusting for age and sex, antisocial [β = 0.23, 95% confidence interval (CI) = 0.19-0.28] and borderline PDs (β = 0.20, 95% CI = 0.14-0.26) were associated strongly with CU. Antisocial (β = 0.26, 95% CI = 0.21-0.31) and borderline PDs (β = 0.12, 95% CI = 0.06-0.18) were also linked strongly to CUD. Genetic risks in antisocial and borderline PD traits explained 32-60% of the total variance in CU and CUD. Dependent and avoidant PDs explained 11 and 16% of the total variance in CU and CUD, respectively., Conclusions: Individual differences in the liability to cannabis use and cannabis use disorder appear to be linked to genetic risks correlated with antisocial and borderline personality disorder traits., (© 2018 Society for the Study of Addiction.)

Borderline Personality Disorder (BPD) is a major mental illness with a lifetime prevalence of approximately 1-3%, characterized by a persistent pattern of instability in relationships, mood, impulse regulation, and sense of self. This results in impulsive self-damaging behavior, high suicide rates, and severe functional impairment. BPD has a complex, multifactorial etiology, resulting from an interaction among genetic and environmental substrates, and has moderate to high heritability based on twin and family studies. However, our understanding of the genetic architecture of BPD is very limited. This is a critical obstacle since genetics can pave the way for identifying new treatment targets and developing preventive and disease-modifying pharmacological treatments which are currently lacking. We review genetic studies in BPD, with a focus on limitations and challenges and future directions. Genetic research in BPD is still in its very early stages compared to other major psychiatric disorders. Most early genetic studies in BPD were non-replicated association studies in small samples, focused on single candidate genes. More recently, there has been one genome-wide linkage study and a genome-wide association study (GWAS) of subclinical BPD traits and a first GWAS in a relatively modest sample of patients fulfilling full diagnostic criteria for the disorder. Although there are adequate animal models for some of the core dimensions of BPD, there is a lack of translational research including data from animal models in BPD. Research in more pioneering fields, such as imaging genetics, deep sequencing and epigenetics, holds promise for elucidating the pathophysiology of BPD and identifying new treatment targets., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Although borderline personality disorder (BPD) traits decline from adolescence to adulthood, comorbid psychopathology such as symptoms of major depressive disorder (MDD), alcohol use disorder (AUD), and drug use disorders (DUDs) likely disrupt this normative decline. Using a longitudinal sample of female twins (N = 1,763), we examined if levels of BPD traits were correlated with changes in MDD, AUD, and DUD symptoms from ages 14 to 24. A parallel process biometric latent growth model examined the contributions of genetic and environmental factors to the relationships between developmental components of these phenotypes. Higher BPD trait levels predicted a greater rate of increase in AUD and DUD symptoms, and higher AUD and DUD symptoms predicted a slower rate of decline of BPD traits from ages 14 to 24. Common genetic influences accounted for the associations between BPD traits and each disorder, as well as the interrelationships of AUD and DUD symptoms. Both genetic and nonshared environmental influences accounted for the correlated levels between BPD traits and MDD symptoms, but solely environmental influences accounted for the correlated changes between the two over time. Results indicate that higher levels of BPD traits may contribute to an earlier onset and faster escalation of AUD and DUD symptoms, and substance use problems slow the normative decline in BPD traits. Overall, our data suggests that primarily genetic influences contribute to the comorbidity between BPD features and substance use disorder symptoms. We discuss our data in the context of two major theories of developmental psychopathology and comorbidity.

Borderline personality disorder (BPD) is a severe and complex mental disease associated with high suicidal tendencies and hospitalization rates. Accumulating evidence suggests that epigenetic mechanisms are implicated in the etiology of BPD. A recent epigenome-wide study identified several novel genes which are epigenetically dysregulated in BPD. Those genes include APBA3 and MCF2. Psychotherapy such as Dialectical Behavior Therapy (DBT), an established treatment for BPD, provides an excellent setting to investigate environmental influences on epigenetic mechanisms in order to identify biomarkers for disease status and therapy success. However, the effects of DBT on epigenetic regulation has only been researched in one previous study analyzing BDNF. In the present study, we aimed to investigate the role of DNA methylation of APBA3 and MCF2 as possible biomarkers for treatment outcome in BPD, whilst validating the previous findings of differential DNA methylation in a cohort of 44 BPD patients and 44 well-matched healthy control individuals. Unexpectedly, we did not detect significant DNA methylation differences between patients and control individuals. However, we found a high correlation between the methylation status of APBA3 and MCF2 and therapy outcome: before DBT treatment, both genes were significantly higher methylated in patients responding to therapy compared to patients that did not respond. Our study is the first to report results pointing to possible predictive epigenetic biomarkers of DBT outcome in BPD patients. Following replication in independent cohorts, our finding could facilitate the development of more personalized therapy concepts for BPD patients by including epigenetic information., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Background and Aims: The DSM-IV personality disorders (PDs) are comorbid with alcohol use disorder (AUD) and with each other. It remains unclear which PD criteria are most likely to drive onset and recurrence of AUD and which are merely confounded with those criteria. We determine which individual PD criteria predict AUD and the degree of underlying genetic and/or environmental aetiology., Design: A prospective observational twin study., Setting: Norway 1999-2011., Participants: A total of 2528 and 2275 Norwegian adult twins in waves 1 and 2 variable-selection analyses, and 2785 in biometric analyses., Measurements: DSM-IV PDs and their 80 criteria were assessed using a structured personal interview, and AUD using the World Health Organization's Composite International Diagnostic Interview., Findings: In a variable-selection analysis, two PD criteria were associated with AUD even after taking all the other criteria into account: criterion 8 of antisocial PD (childhood conduct disorder) and criterion 4 of borderline PD (self-damaging impulsive behaviours). Adjusting for each other, their respective odds ratios were 3.4 [confidence interval (CI) = 2.1-5.4] and 5.0 (CI = 3.3-7.7). Endorsement strength of the criteria was associated with AUD in a dose-response manner and they explained 5.5% of variation in AUD risk-more than the full diagnoses of antisocial and borderline PDs together (0.5%). The association between borderline criterion 4 and AUD 10 years later derived mainly from their overlapping genetic factors, whereas the association between antisocial criterion 8 and AUD 10 years later was due to both genetic and non-genetic factors., Conclusions: Conduct disorder and self-harming impulsivity are the foremost risk traits for alcohol use disorder among the 80 personality disorder criteria of DSM-IV, predicting alcohol use disorder more effectively than personality disorder diagnoses. The twin-study analysis suggested that conduct disorder represents a joint genetic and developmental risk for alcohol use disorder and that impulsivity is a genetic risk., (© 2017 Society for the Study of Addiction.)

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10 -7 ) and PKP4 (P=8.67 × 10 -7 ); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, P FDR =0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (r g =0.28 [P=2.99 × 10 -3 ]), SCZ (r g =0.34 [P=4.37 × 10 -5 ]) and MDD (r g =0.57 [P=1.04 × 10 -3 ]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.

The Lasso is a shrinkage regression method that is widely used for variable selection in statistical genetics. Commonly, K-fold cross-validation is used to fit a Lasso model. This is sometimes followed by using bootstrap confidence intervals to improve precision in the resulting variable selections. Nesting cross-validation within bootstrapping could provide further improvements in precision, but this has not been investigated systematically. We performed simulation studies of Lasso variable selection precision (VSP) with and without nesting cross-validation within bootstrapping. Data were simulated to represent genomic data under a polygenic model as well as under a model with effect sizes representative of typical GWAS results. We compared these approaches to each other as well as to software defaults for the Lasso. Nested cross-validation had the most precise variable selection at small effect sizes. At larger effect sizes, there was no advantage to nesting. We illustrated the nested approach with empirical data comprising SNPs and SNP-SNP interactions from the most significant SNPs in a GWAS of borderline personality symptoms. In the empirical example, we found that the default Lasso selected low-reliability SNPs and interactions which were excluded by bootstrapping.

Borderline personality disorder (BPD) is a serious condition involving emotion dysregulation. Past research has identified BPD-associated differences within fronto-limbic circuitry during conditions of processing negative emotion. Functional magnetic resonance imaging (fMRI) paradigms that incorporate overt and covert (masked) presentations of emotional stimuli can provide complementary information about neural systems underlying emotion processing (e.g., both slow [overt] and fast [covert; automatic] processing pathways). This study examined brain activation during processing of overt and covert presentations of emotional faces in 12 women with BPD and 12 age-matched healthy controls. To assess a range of emotional valence and arousal, we examined responses to fear, happy and neutral expressions. All participants underwent an fMRI scanning session in which participants passively viewed emotional faces. Scanning sessions consisted of 5 runs including: (1) Overt Fear (OF) versus Neutral (N), (2) Covert Fear (CF) versus Covert Neutral (CN), (3) Overt Happy (OH) versus N, (4) Covert Happy (CH) versus CN, and (5) N versus fixation. We compared whole-brain activation between groups for each run. In response to overt fear, BPD patients showed greater activation both in left amygdala and in several frontal cortical regions. There were no significant differences in brain activation in response to overt happy faces. In response to covert fear and covert happy stimuli, the BPD group also showed greater activation than controls in several regions including frontal and temporal cortical regions, as well as cerebellum and thalamus. These findings add to prior reports suggesting increased amygdala activation in BPD, but we found this only in the overt fear versus fixation condition. In this sample, BPD patients showed hyper-activation, rather than hypo-activation, of cortical regulatory regions during overt fear. Enhanced cortical recruitment in response to covert fear and happy faces in BPD could reflect a more extended response system in which stimuli that typically only activate automatic pathways are additionally tapping into cortical regulatory systems. The observation of this pattern both in response to fear and in response to happy presentations suggests that the effect of arousal may be as or more impactful than the effect of emotional valence.

Current knowledge suggests that borderline personality disorder (BPD) results from the interaction between genetic and environmental factors. Research has mainly focused on monoaminergic genetic variants and their modulation by traumatic events, especially those occurring during childhood. However, to the best of our knowledge, there are no studies on the genetics of hypothalamus-pituitary-adrenal (HPA) axis, despite its vulnerability to early stress and its involvement in BPD pathogenesis. The aim of this study was to investigate the contribution of genetic variants in the HPA axis and to explore the modulating effect of childhood trauma in a large sample of BPD patients and controls. DNA was obtained from a sample of 481 subjects with BPD and 442 controls. Case-control differences in allelic frequencies of 47 polymorphisms in 10 HPA axis genes were analysed. Modulation of genetic associations by the presence of childhood trauma was also investigated by dividing the sample into three groups: BPD with trauma, BPD without trauma and controls. Two FKBP5 polymorphisms (rs4713902-C and rs9470079-A) showed significant associations with BPD. There were also associations between BPD and haplotype combinations of the genes FKBP5 and CRHR1. Two FKBP5 alleles (rs3798347-T and rs10947563-A) were more frequent in BPD subjects with history of physical abuse and emotional neglect and two CRHR2 variants (rs4722999-C and rs12701020-C) in BPD subjects with sexual and physical abuse. Our findings suggest a contribution of HPA axis genetic variants to BPD pathogenesis and reinforce the hypothesis of the modulating effect of childhood trauma in the development of this disorder.

Borderline personality disorder (BPD) is a serious psychic disease with a high risk for suicide. DNA methylation is a hallmark for aberrant epigenetic regulation and could be involved in the etiology of BPD. Previously, it has been reported that increased DNA methylation of neuropsychiatric genes is found in the blood of patients with BPD compared to healthy controls. Here, we analyzed DNA methylation patterns of the ribosomal RNA gene (rDNA promoter region and 5'-external transcribed spacer/5'ETS) and the promoter of the proline rich membrane anchor 1 gene (PRIMA1) in peripheral blood samples of 24 female patients (mean age (33 ± 11) years) diagnosed with DSM-IV BPD and in 11 female controls (mean age (32 ± 7) years). A significant aberrant methylation of rDNA and PRIMA1 was revealed for BPD patients using pyrosequencing. For the promoter of PRIMA1, the average methylation of six CpG sites was 1.6-fold higher in BPD patients compared to controls. In contrast, the methylation levels of the rDNA promoter region and the 5'ETS were significantly lower (0.9-fold) in patients with BPD compared to controls. Thus, for nine CpGs located in the rDNA promoter region and for four CpGs at the 5'ETS decreased methylation was found in peripheral blood of patients compared to controls. Our results suggest that aberrant methylation of rDNA and PRIMA1 is associated with the pathogenesis of BPD.

Background: Serotonin 3A receptor (5-HT3A R) is associated at the genetic and epigenetic levels with a variety of psychiatric disorders and interacts with early-life stress such as childhood maltreatment. We studied the impact of childhood maltreatment on the methylation status of the 5-HT3A R and its association with clinical severity outcomes in relation with a functional genetic polymorphism., Methods: Clinical severity indexes of 346 bipolar, borderline personality, and adult attention deficit hyperactivity disorders patients were tested for association with the DNA methylation status of eight 5-HT3A R gene CpGs. Relationship between the functional variant rs1062613 (C > T) and methylation status on severity of the disorders were also assessed., Results: Childhood maltreatment was associated with higher severity of the disease (higher number of mood episodes, history of suicide attempts, hospitalization, and younger age at onset) across disorders and within each individual disorder. This effect was mediated by two 5-HT3A R CpGs. Compared to T allele carriers, CC carriers had higher methylation status at one CpG located 1 bp upstream of this variant., Conclusions: This study shows that epigenetic modification of the 5-HT3A R is involved in the mechanism underlying the relationship between maltreatment in childhood and the severity of several psychiatric disorders in adulthood., (© 2015 Wiley Periodicals, Inc.)

[Correction Notice: An Erratum for this article was reported in Vol 28(1) of Psychological Assessment (see record 2015-54029-001). The FFI-BPD values for Sample 3 in Table 2 should read 1.42 (0.44), 0.83.] The aim of the current study was to examine the reliability and validity of a trait-based assessment of borderline personality disorder (BPD) using the NEO Five-Factor Inventory. Correlations between the Five-Factor Inventory-BPD composite (FFI-BPD) and explicit measures of BPD were examined across 6 samples, including undergraduate, community, and clinical samples. The median correlation was .60, which was nearly identical to the correlation between measures of BPD and a BPD composite generated from the full Revised NEO Personality Inventory (i.e., NEO-BPD; r = .61). Correlations between FFI-BPD and relevant measures of psychiatric symptomatology and etiology (e.g., childhood abuse, drug use, depression, and personality disorders) were also examined and compared to those generated using explicit measures of BPD and NEO-BPD. As expected, the FFI-BPD composite correlated most strongly with measures associated with high levels of Neuroticism, such as depression, anxiety, and emotion dysregulation, and the pattern of correlations generated using the FFI-BPD was highly similar to those generated using explicit measures of BPD and NEO-BPD. Finally, genetic analyses estimated that FFI-BPD is 44% heritable, which is comparable to meta-analytic research examining genetics associated with BPD, and revealed that 71% of the genetic influences are shared between FFI-BPD and a self-report measure assessing BPD (Personality Assessment Inventory-Borderline subscale; Morey, 1991). Generally, these results support the use of FFI-BPD as a reasonable proxy for BPD, which has considerable implications, particularly for potential gene-finding efforts in large, epidemiological datasets that include the NEO FFI., ((c) 2016 APA, all rights reserved).)

Background: Antisocial personality disorder (ASPD) and borderline personality disorder (BPD) share genetic and environmental risk factors. Little is known about the temporal stability of these etiological factors in adulthood., Method: DSM-IV criteria for ASPD and BPD were assessed using structured interviews in 2282 Norwegian twins in early adulthood and again approximately 10 years later. Longitudinal biometric models were used to analyze the number of endorsed criteria., Results: The mean criterion count for ASPD and BPD decreased 40% and 28%, respectively, from early to middle adulthood. Rank-order stability was 0.58 for ASPD and 0.45 for BPD. The best-fitting longitudinal twin model included only genetic and individual-specific environmental factors. Genetic effects, both those shared by ASPD and BPD, and those specific to each disorder remained completely stable. The unique environmental effects, however, changed substantially, with a correlation across time of 0.19 for the shared effects, and 0.39 and 0.15, respectively, for those specific to ASPD and BPD. Genetic effects accounted for 71% and 72% of the stability over time for ASPD and BPD, respectively. The genetic and environmental correlations between ASPD and BPD were 0.73, and 0.43, respectively, at both time points., Conclusion: ASPD and BPD traits were moderately stable from early to middle adulthood, mostly due to genetic risk factors which did not change over the 10-year assessment period. Environmental risk factors were mostly transient, and appear to be the main source of phenotypic change. Genetic liability factors were, to a large extent, shared by ASPD and BPD.

This study investigated the possible association of 40 polymorphisms within 4 noradrenergic genes with BPD risk and the modulating effect of childhood trauma on these associations in 481 BPD subjects and 442 controls. COMT rs5993882, DBH rs77905 and SLC6A2 rs1814270 showed associations with BPD, which were modulated by childhood trauma. However, none of these findings survived Bonferroni correction. Further investigation is needed to clarify the involvement of these genes in BPD pathogenesis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)