The borderline diagnosis III: identifying endophenotypes for genetic studies

doi:10.1016/S0006-3223(02)01326-4

Biological Psychiatry

Volume 51, Issue 12, 15 June 2002, Pages 964-968

https://doi.org/10.1016/S0006-3223(02)01326-4 Get rights and content

Abstract

Although it is generally acknowledged that borderline personality disorder (BPD) has a complex, multifactorial etiology with interacting genetic and environmental substrates, the specific genetic underpinnings of this disorder have not been extensively investigated. Family aggregation studies suggest the heritability for BPD as a diagnosis, but the genetic basis for this disorder may be stronger for dimensions such as impulsivity/aggression and affective instability than for the diagnostic criteria itself. Family, adoptive, and twin studies also converge to support an underlying genetic component to the disorder. An endophenotypic approach to defining the genetics of this complex disorder may be called for. Twin studies in an epidemiologic, non-clinically ascertained sample using both diagnostic measures and laboratory measures that can be operationalized, including neuropsychologic, psychophysiologic, and operationalized behavioral tests, may be useful. Large-scale family studies of clinically ascertained samples with careful diagnostic demarcation and measurement of endophenotypes in probands and relatives may also prove to be a promising approach. The use of laboratory paradigms for measures of aggression and affective instability are discussed in the context of such endophenotypic approaches.

Introduction

Although there is general consensus that borderline personality disorder (BPD) has a multifactorial etiology including both genetic and environmental influences, there has been little systematic research into the specific genetic and environmental antecedents to this disorder. In part, the interpersonal and psychodynamic considerations that provided the original impetus to define this disorder and address its treatments may not lend themselves as easily to classic genetic approaches as more simply defined disorders; however, if the BPD diagnosis is reframed in terms of more specific, measurable, presumably biologically based endophenotypes, the possibilities of identification of genetic predisposing factors might be considerably improved. Such a reframing that might generate fruitful genetic investigation into this disorder might then encourage more rigorous research, attracting investigators to what has heretofore been seen as a somewhat “fuzzy” diagnosis from a genetic point of view. A better understanding of the genetics of this disorder might improve the prospects of targeted interventions for more homogeneous subsets of borderline patients characterized by specific genetic vulnerabilities.

Section snippets

Family aggregation studies of BPD

Currently there is substantial evidence for familial aggregation of BPD or traits as a greater frequency of the diagnosis of BPD or borderline traits are seen in the relatives of probands with BPD than in comparison groups Baron et al 1985, Links et al 1998, Loranger et al 1982, Pope et al 1983, Reich 1989, Silverman et al 1991, Soloff and Millward 1983, Torgersen 2000, Zanarini et al 1988. The frequency of BPD features among first-degree relatives of BPD probands varies from study to study,

Heritability of personality disorder

A number of studies have examined heritability of different facets of personality, although most have not focused on the personality disorder diagnoses. Studies of twins reared together and apart suggest a strong genetic influence on personality dimensions such as neuroticism and extraversion Pedersen et al 1991, Tellegen et al 1988. Adoption studies of samples with diagnosed personality disorders have demonstrated a genetic influence on the development of antisocial personality disorder

Strategies for genetic studies of BPD

Ideally, the most definitive study would identify a large number of twins in an epidemiologic nonclinically ascertained sample but with a sufficient prevalence of probands with the diagnoses of BPD to achieve substantial power for genetic studies. The twins could then be systematically identified and recruited for the study. In this kind of study, subjects would be evaluated with regard to clinical phenotype by diagnostic interview, self-report measures of personality traits, and laboratory

Endophenotypic/dimensional approaches

If BPD is conceptualized as a personality disorder emerging from the interaction of underlying genetically based traits Siever and Davis 1991, Livesley et al 1992, the prospect for identifying underlying endophenotypes becomes potentially more feasible. Endophenotypes represent measurable characteristics that reflect an underlying genotype that may be more closely related to that genotype than the diagnostic category itself. The endophenotype approach is being successfully applied to the

Acknowledgements

This paper was commissioned by and written with the support of the Board of Trustees of the Borderline Personality Disorder Research Foundation (BPDRF) and aspects of this work were presented and discussed at the First Annual Scientific Meeting of the Foundation, July 13–14, 2000. The authors are or were members of or consultants to the Scientific Advisory Board of the BPDRF. The authors appreciate the helpful comments of Steven Hyman, M.D.

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Borderline personality disorder (BPD) is characterized by greater intensity of reactions to unpleasant emotional cues and a slower-than-normal return of these responses to baseline. Habituation is defined as decreased response to repeated stimulation. Affect-modulated startle (AMS), a translational psychophysiological approach, is mediated by the amygdala and used to study emotion processing in both humans and animals. This is the first study to examine the specificity of habituation anomalies in BPD during passive emotional and neutral picture processing.
A total of 90 participants were studied: patients with BPD (n = 35), patients with schizotypal personality disorder (n = 26; included as a psychopathological comparison group), and healthy control subjects (n = 29). Participants received rigorous clinical assessments, and patients were unmedicated. AMS was examined during a series of intermixed unpleasant, neutral, and pleasant pictures.
Compared with the other groups, patients with BPD showed greater overall AMS during unpleasant pictures and prolonged habituation of startle amplitude during unpleasant pictures from early to later trials. The groups did not differ in AMS during neutral or pleasant pictures or self-reported picture valence. Among the patients with BPD, prolonged habituation to unpleasant pictures was associated with greater symptom severity and suicidal/self-harming behavior.
These findings 1) indicate that abnormal processing of and habituation to unpleasant pictures is observed in BPD but not schizotypal personality disorder, suggesting that these deficits are not simply characteristics of personality disorders in general; 2) are consistent with studies showing deficient amygdala habituation to unpleasant pictures in BPD; and 3) have significant implications for clinical assessment and treatment of BPD, e.g., alternative therapies for BPD such as gradual exposure to unpleasant emotional stimuli or amygdala neurofeedback may aid habituation deficits.
Diagnostic accuracy of DSM-5 borderline personality disorder criteria: Toward an optimized criteria set
2021, Journal of Affective Disorders
The polythetic system used by the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) for diagnosing borderline personality disorders (BPD) is far from optimal; however, accumulated research and clinical data are strong enough to warrant ongoing utilization. This study examined diagnostic efficiency of the nine DSM-IV BPD criteria, then explored the feasibility of an optimized criteria set in classifying BPD.
Adults (N=1,623) completed the Structured Clinical Interviews for DSM-IV Axis II Disorders resulting in a BPD group (n=352) and an inpatient psychiatric control group (PC) with no personality disorders (n=1,271). Receiver operator characteristics and diagnostic efficiency statistics were calculated to ascertain the relative diagnostic efficiency of each DSM-5 BPD criterion in classifying BPD cases.
Affective instability (Criterion 6) evidenced the strongest capacity to differentiate the groups (AUC = .84, SE = .01, p < .0001). Abandonment fears (Criterion 1), unstable relationships (Criterion 2), identity disturbance (Criterion 3), impulsivity (Criterion 4), and chronic emptiness (Criterion 7) yielded good-to-moderate discrimination (AUC range = .75-.79). A composite index of these six criteria yielded excellent accuracy (AUC = .98, SE = .002, p < .0001), sensitivity (SN=.99), and specificity (SP=.90).
The current findings add to evidence that affective instability is a useful gate criterion for screening, and the optimized criteria set evidences equivalent accuracy to the original 9 criteria, with a substantial reduction in estimated heterogeneity (from 256 combinations with the original set to 42 combinations with the optimized set).
A systematic review of structural MRI investigations within borderline personality disorder: Identification of key psychological variables of interest going forward
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Existing models of Borderline Personality Disorder (BPD) suggest that a combination of genetic vulnerability, childhood trauma, and disrupted attachment can lead to the marked emotional lability, impulsivity and interpersonal difficulties observed clinically. Brain structural differences in frontal, limbic and hippocampal regions have been reported in BPD. Less clear is how specific psychological factors relate to these structural differences, and how consistently this is found across studies. This was the focus of the present review. Eighteen studies published between 2004 and 2018 met inclusion criteria encompassing 990 participants. Study quality was assessed using the Nottingham-Ottawa Scale. We also introduce a newly devised scale to assess MRI reporting quality. The most frequently investigated psychological variable were impulsivity (9 studies), depression (8), trauma (6), aggression (6), severity of symptoms (3), global functioning, abuse and dissociation (2). Study quality varied, however, a trend was observed where newer studies were higher in reporting quality. Impulsivity demonstrated greater association with frontal structures, trauma related to the hypothalamus and limbic systems, and aggression with hippocampal and frontal structures. The present review recommends greater exploration of neurocognitive and psychosis-related features such as delusions, paranoia and voice-hearing in future studies, and to investigate cortical changes in longitudinal designs.
The Neurobiology of Borderline Personality Disorder
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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.
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This study investigated psychophysiological and subjective emotional responses to an affective startle modulation paradigm in first-presentation borderline personality disorder (BPD). Twenty BPD and 20 healthy control participants, aged 15–24 years, viewed a set of standardized pictures with pleasant, neutral, or unpleasant valence, and were instructed to either “maintain” or “suppress” their emotional response to the stimuli. Despite showing markedly higher levels of baseline distress on self-report questionnaires, BPD participants had significantly lower skin conductance responses and showed an absence of the fear potentiated startle response during early picture processing. Both groups showed similar startle responses later in picture processing, and when instructed to “maintain” or “suppress” their emotions. BPD participants were hypo-responsive to aversive stimuli during early processing, and did not react with more intense emotional responses to affective stimuli or show a diminished ability to regulate their responses. These results might be consistent with the finding that hypersensitivity of emotional response in BPD is specific to stimuli with themes of particular relevance to this disorder, such as rejection and abandonment.

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ReviewThe borderline diagnosis III: identifying endophenotypes for genetic studies

Abstract

Introduction

Section snippets

Family aggregation studies of BPD

Heritability of personality disorder

Strategies for genetic studies of BPD

Endophenotypic/dimensional approaches

Acknowledgements

Familial transmission of schizotypal borderline personality disorders

Am J Psychiatry

Human studies of prepulse inhibition of startleNormal subjects, patient groups, and pharmacological studies

Psychopharmacology (Berl)

An adoptive study of attention deficit/hyperactivity/aggression and their relationship to adult antisocial personality

Psychiatry

Effects of smoking different doses of nicotine on human aggressive behavior

Psychopharmacology

Studies of violent and nonviolent male paroleesI. Laboratory and psychometric measurements of aggression

Biol Psychiatry

Human aggressive responses maintained by avoidance or escape from point loss

J Exp Anal Behav

Heritability of aggression and irritabilityA twin study of the Buss-Durkee Aggression Scales in adult male subjects

Biol Psychiatry

Heritability of irritable impulsivenessA study of twins reared together and apart

Psychiatry Res

Serotonergic studies in patients with affective and personality disordersCorrelates with suicidal and impulsive aggressive behavior

Arch Gen Psychiatry

The continuous performance task, Identical Pairs version (CPT-IP) INew findings about sustained attention in normal families

Psychiatry Res

Neurochemical and cognitive phenotypes for genetic studies of schizophrenia

J Biol Psychiatry

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Effect of COMT Vall08/158 Met genotype on frontal lobe function and risk for schizophrenia

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Psychiatric geneticsSearch for phenotypes

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Biol Psychiatry

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Biol Psychiatry

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ImpulsivityCore aspect of borderline personality disorder

J Personal Disord

Review
The borderline diagnosis III: identifying endophenotypes for genetic studies