Symptoms of BPD are typically categorized into 4 phenotypes—the “borderline sectors”—that coexist in varying degrees within individuals with BPD and, often, in their family members.
1) The affective sector includes emotions that are characteristically challenging for patients with BPD. These include loneliness, emptiness, inappropriate and intense anger, and quick fluctuations in mood.
2) The interpersonal sector of BPD refers to these patients’ penchant for intense and volatile relationships and their tendency to be at once manipulative, entitled, and devaluing as well as dependent, idealizing, and fearful of abandonment.
3) The cognitive sector encompasses distressing perceptual disturbances, including dissociation and paranoia during times of stress.
4) The behavioral sector of BPD describes risky, impulsive behaviors as well as self-injury and threats of self-harm common in this population.
It is thought that the phenotypic expression of each of these sectors represents a confluence of genetic and environmental influences.
In 2011, Gunderson and colleagues7 conducted a family study to investigate the degree to which BPD clustered within families as well as how much of this clustering was attributable to genetic predispositions for borderline sectors as opposed to the disorder itself. In their study, the prevalence of BPD among relatives of probands with BPD was 14.1% compared with 4.9% in the family members of controls. The relative risk that if one family member had BPD, so too would another was 3.9 (95% confidence interval, 1.7 - 9.0) when compared with controls. Aggregation of BPD in families occurred in this study more than aggregation of any of the sectors, which supports a common pathway model of inheritance. In this model, borderline traits concentrate in families because of a genetic predisposition for the disorder rather than for the sectors themselves.
While family studies provide convincing evidence that BPD is inherited, twin studies have been invaluable to the study of heritability, the phenotypic variance attributable to genetic rather than environmental influences. A 2011 web-based study looked at the heritability of the disorder using responses to well-validated personality questionnaires.8 Study participants included 542 same-sex twin pairs, 441 of whom were monozygotic. The 4 dimensions of BPD loaded as one factor and provided further support for the common pathway model used by Gunderson and colleagues.7 Findings from the study indicate a heritability of 60%. This is similar to other twin and extended twin studies that estimate heritability to fall somewhere between 40% and 70%.
Molecular genetic studies have focused on the rate-limiting enzyme in serotonin (5-hydroxytryptamine [5-HT]) synthesis, as well as 5-HT receptor and transporter genes. 5-HT derives from tryptophan through a process mediated by tryptophan hydroxylase. Tryptophan hydroxylase 2 (TPH2) is a neuron-specific enzyme responsible for producing 5-HT in the CNS. Single nucleotide polymorphism and haplotype analyses have revealed that a gene encoding a specific TPH2 isoform is associated with higher rates of anxiety, depression, and suicidal behavior.
In 2010, Perez-Rodriguez and colleagues9 genotyped patients with BPD and compared them with patients who had other personality disorders and healthy controls. They found that the previously identified TPH2 risk haplotype was more prevalent in patients with BPD (P < .05) than in controls. Subjects with the TPH2 risk haplotype exhibited higher aggression and emotional lability scores and increased suicidal behavior.
Of the serotonin receptor genes, polymorphisms in 5HTR2A and 5HTR2C have been most closely correlated with BPD. Variants of the 5HT2A receptor are known to correlate with suicide, affective lability, and impulse control. 5HTR2A polymorphisms correlate with borderline traits.10
Ni and colleagues11 analyzed polymorphisms in serotonin receptor genes in patients with BPD and matched controls. Their results showed an association between BPD and the 5HTR2C gene. Moreover, subjects who were homozygous for the HTR2C rs6318 G/G genotype had a higher frequency of the TPH2 “risk” haplotype. Taken together, the data suggest that a TPH2 “risk” haplotype may change serotonin in a way that predisposes to BPD. Patients may be more susceptible to a specific variant of 5HTR2C, which may further contribute to the pathogenesis of BPD.
Drs Pier, Marin, and Goodman are psychiatrists at Icahn School of Medicine at Mount Sinai in New York. Dr Pier is a third-year resident, Dr Marin is a second-year resident, and Dr Goodman is Clinical Professor. Dr Goodman is also the Director of Dialectical Behavioral Therapy & Suicide Prevention Studies Clinical and Research Program at the James J. Peters Veterans Affairs Medical Center, and Mental Illness Research Education and Clinical Center (MIRECC), in Veterans Integrated Service Network (VISN) 3. Ms Wilsnack is a Research Coordinator for the VISN 3 MIRECC. The authors report no conflicts of interest concerning the subject matter of this article.
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