dcyphr | Current Knowledge on Gene-Environment Interactions in Personality Disorders: An Update


The authors reviewed the gene-environment interactions (GxE) and epigenetic factors in borderline personality disorder (BPD), mainly, as well as avoidant, schizotypal, and antisocial personality disorders. Childhood sexual and physical abuse were found to mediate the expression of susceptibility genes in borderline personality disorder. Epigenetic (i.e., environmental) alterations to brain development and genes involved with stress were found to explain the relationship between BPD and challenges early in life. The results suggest possible biological treatment targets for personality disorders, which are known to be chronic and lack any pharmacological treatments.


The present understanding of the genetic risk for BPD is that it is caused by a synthesis of many variants spread throughout the genome, each of which increases the risk for developing BPD. Environmental influences play a large role in the emergence of psychiatric disorders, even in highly heritable ones (i.e., schizophrenia, autism).

The GxE approach posits that environmental influences are responsible for the genesis of disorders with genes changing individual susceptibilities to environmental factors. This is assuming that one’s genetic predispositions are expressed differently in different environments, and environmental influences are ‘felt’ differently according to one’s genetic predispositions. The main evidence for the gene-environment interaction approach is the observed heterogeneity of responses to environmental influences that cause psychiatric disorders.

Borderline Personality Disorder

Genetics and Environment in BPD

BPD is the most commonly diagnosed personality disorder, marked by emotional instability, dysfunctional social relationships, and self-destructive, impulsive behavior. BPD has a high mortality rate (8.3%) and raised healthcare costs, so it has been pressing for researchers to find out more about it. Most studies on BPD have mistakenly viewed gene-environment interactions as being independent. Candidate genes in certain neurotransmission centers (i.e., serotoninergic) have been widely studied, but proven unsuccessful in finding associations with BPD diagnostic features. This suggests research on susceptibility should focus not on “vulnerability genes” but on plasticity genes, which are in line with the GxE approach. Moreover, genome-wide association studies (GWAS), rather than focus on candidate genes, have revealed more promising genes.

Gene-Environment Interaction Studies in BPD

Although environmental factors such as childhood sexual abuse and neglect have been established as influencing BPD, few GxE studies have been conducted. These studies assert that certain “susceptibility” genes to BPD are expressed in response to certain environmental factors or tribulations. Possible susceptibility genes are as follows:

  • Serotonin transporter promoter (5-HTTLPR)
  • Catechol-O-methyltransferase (COMT)
  • Val158Met polymorphism
  • Brain-derived neurotrophic factor (BDNF)
  • Val66Met polymorphism
  • TPH1 polymorphism
  • Oxytocin receptor gene (OXTR rs53576) and FKBP5 gene
  • HPA genetic polymorphisms
  • Gene-environment correlations (rGE)
  • Epigenetic Modifications in BPD

Epigenetics describes the resulting gene expression of an interaction between a gene and the environment without changing the DNA sequence of the gene. This is a heritable alteration that is stable, but reversible and acts as an adaptive biological response to one’s environment. Implicated genes are as follows:

  • Glucocorticoid receptor (GR) gene (NR3C1)
  • Serotonin 3A receptor gene
  • Brain-derived neurotrophic factor (BDNF) gene
  • Dopamine receptor D2 gene
  • Ribosomal DNA gene
  • Multigene/genome-wide investigations

Methylation, a biological process that can change the activity of a DNA segment without changing its sequence, of these genes revealed many associations and correlations with regard to BPD.

Future directions

BPD affects 2-5.9% of the general population. The nascent evidence on the role of GxE in BPD poses new possibilities for its treatment, especially those taking into account epigenetics. This is even more pressing considering the lack of pharmacological treatments for BPD.

Other personality disorders

Antisocial personality disorder

ASPD, as defined by DSM-IV-TR, includes a chronic pattern (beginning in adolescence and continuing into adulthood) of law-breaking or violation of the rights of others, along with impulsivity/failure to plan ahead, irresponsibility, recklessness, deceitfulness, irritability/aggressiveness and a lack of remorse for repeated wrongdoing.

The monoamine oxidase A (MAOA)-encoding gene and serotonin transporter gene promoter polymorphism (5-HTTLPR) have been identified as having associations with antisocial behaviors.

Schizotypal Personality Disorder

Schizotypal Personality Disorder (SPD) consists of problems with interpersonal relations that result from social detachment, psychotic personality traits (i.e., eccentricity), and confusing boundaries with others.

SPD is closely related to schizophrenia, but little is known about its genetic bases. One study reported that the p250GAP gene polymorphism may be involved in the susceptibility to both schizophrenia and schizotypal personality traits.

Avoidant Personality Disorder

Avoidant personality disorder (AvPD) features an avoidance of many social situations that result from the combination of feelings of inferiority and sensitivity to negative evaluations by others about the self. It is viewed as being very similar to social anxiety disorder.

Studies about environmental influences on the emergence of AvPD are uncommon, but preliminary evidence suggests that parental neglect and/or abuse may increase the likelihood of its development. Some polymorphisms in genes regulating serotonin and dopaminergic systems provide evidence of heritability (transmissible from parent to child) in AvPD.


Environmental risk factors like histories of childhood maltreatment and abuse have been shown to play a significant role in the emergence of BPD, but formal studies exploring the interaction environmental and genetic factors have only been explored fairly recently. Epigenetic changes are thought to be the intermediary mechanism linking environmental experiences to biological changes that play key roles in personality disorders. “Susceptibility genes” to personality disorders, namely BPD, or their traits may be expressed under specific conditions in response to specific challenges. Most of the GxE studies have focused on negative environmental factors such as childhood sexual abuse, so it is necessary for future studies to evaluate the impacts of positive environments on susceptibility genes in order to get a more comprehensive understanding of gene-environment interactions.

Epigenetic changes are reversible, so research here invites the emergence of new treatments and medications for these personality disorders. Particular attention to childhood interactions with parents (i.e., childhood trauma) is important in preventing the emergence of these severe personality disorders.