Borderline personality disorder (BPD) is a severe mental disorder with a high mortality rate as a result of suicide and impulsive behavior . The core symptoms include emotional disturbance (affective instability, intense anger, chronic feelings of emptiness), disturbed cognition (identity disturbance, transient paranoid ideation or dissociative symptoms), impulsivity (suicidal or self-mutilating behavior, or other self-damaging behaviors, such as substance abuse, reckless driving, unsafe sex, spending sprees, binge eating), and interpersonal problems (intense unstable relationships, fear of abandonment). Interaction of multiple genetic factors and distressing childhood experiences has been suggested in the development of emotional dysregulation and impulsivity, leading to BPD symptoms . The first family studies indicated substantial genetic underpinnings , and twin studies showed 42-69% heritability estimates [3, 4]. Animal and human studies have indicated that reduced serotonin function and increased norepinephrine activity in the brain lead to aggressive and impulsive behavior . Although several impulsive behaviors (e.g. ADHD: Attention Deficit Hyperactivity Disorder or substance abuse) have been linked to altered dopamine function, involvement of the dopamine system in BPD has been circumstantial. The main supporting evidence, thus far, comes from the therapeutic effect of D2 receptor blocking antipsychotic drugs .
Hitherto, only a couple of workgroups have studied dopamine system related polymorphisms in BPD. The first genetic association study showing a dopaminergic effect on BPD was conducted among depressed patients . The 9-repeat allele of the dopamine transporter gene (DAT1, SLC6A3) showed significant association with BPD, even when childhood abuse and neglect, and borderline temperament were included in the analyses. A recent study reported an over-representation of the low activity Met/Met genotype of the catechol-O-methyl-transferase (COMT) gene in 161 BPD patients . Since COMT metabolizes catecholamines, these findings suggest that altered dopamine and/or norepinephrine neurotransmission might be a contributing factor in the development of BPD. In spite of the pharmacological evidence, dopamine D2 receptor (DRD2) polymorphisms have not been studied in relation to BPD. Dopamine D4 receptor (DRD4) might be another candidate, because of the preferential expression of this D2-family member in the prefrontal cortex  and its well-established role in ADHD  as well its possible involvement in human personality traits of novelty-seeking and impulsivity . However, a pilot study of 39 BPD patients did not show any significant effect of DRD4 polymorphisms .
We aimed to investigate the possible involvement of dopaminergic polymorphisms in the etiology of impulsive self- and other-damaging behaviors (assessed by borderline and antisocial traits) in a previously studied US community-based sample of 99 young adults from low-to-moderate income families . This group could be regarded as an at-risk population, because it has been shown that low family socioeconomic status confers a risk for BPD  and low educational or occupational status is an important risk factor for suicide attempts . In this sample 4% were diagnosed with BPD and 7% with antisocial personality disorder (APD) in young adulthood, showing a prevalence 2-3 times higher compared to the general community (BPD: 1-2%, APD: 2-3%) [16, 17]. A group of 136 Hungarian patients with mood disorder served as the replication sample for findings related to borderline traits, because borderline diagnosis, as well as borderline traits, have a high prevalence rate among psychiatric inpatients (15%) .
In addition to the previously indicated dopaminergic polymorphisms, namely the 40 bp VNTR (variable number of tandem repeats) of the DAT1 gene, and the Val158Met polymorphism of the COMT gene, the most commonly investigated DRD2 and DRD4 polymorphisms were genotyped. The DRD2 TaqIA polymorphism was identified during the chromosomal localization of the gene. However, this single nucleotide polymorphism (SNP) is in the 3' untranslated region, 10 kilobase downstream from the DRD2 gene, actually in the neighboring ANKK1 gene . Nevertheless, four independent workgroups showed reduced D2 receptor density of the minor A1-allele carriers [19–22], and only one reported a negative finding . Therefore, this polymorphism might be a good marker for DRD2 density in the brain. The DRD2 gene has been associated with alcoholism and other addictive disorders , and is hypothesized to be a reinforcement or reward gene. Recently, two studies showed an association between the DRD2/ANKK1 A1-allele and impulsive behavior among healthy young adults [25, 26]. To further assess the possible involvement of the DRD2 gene, two additional SNPs (TaqIB from intron 1 and TaqID from intron 2) were selected for genotyping.
Within the DRD4 gene, the 48 bp VNTR in exon III has received the most interest in psychiatric genetics [10, 11]. Recent studies suggested that the 7-repeat allele of the DRD4 gene may result in reduced DRD4 expression, influencing RNA stability . Therefore, other polymorphisms located in the promoter region of the DRD4 gene with predictable or proven effects on gene expression might also be worthwhile to study. The -616 C/G and -521 C/T SNPs, and a 120 bp duplication in the 5' untranslated region of the DRD4 gene have been extensively studied in dopamine-related child psychiatric disorders, such as ADHD . Therefore, we have analyzed these four DRD4 gene variants in the two samples.
Since gene × gene and gene × environment interactions may be important in the development of psychiatric disorders, exploratory analyses investigating previously reported interactions in the impulsive behavior literature were also conducted. For example, DRD2 A1-allele × DRD4 7-repeat allele interaction has been reported for impulsivity , sensation seeking , and antisocial behavior , and DRD4 VNTR × DAT1 VNTR interaction has been reported for behavioral inhibition . Also, environmental risk and protective factors, such as maternal insensitivity or intervention promoting positive parenting, were shown to interact with the DRD4 7-repeat allele on child externalizing (oppositional, aggressive) behavior [31, 32].