Borderline Personality Disorder (BPD) is a severe mental illness characterized by emotional instability, impulsive behaviour, a disturbed self-image and considerable difficulties in interpersonal relationships. It often begins in adolescence and affects around 0.9 to 1.9 percent of the population in Western countries – with significantly higher diagnosis rates among women. Many affected persons show self-harming behavior, suicidal thoughts or repeated suicide attempts. Despite the high psychological burden, frequent concomitant illnesses and lack of specific medication, the biological causes are still poorly understood.

11 risk regions and nine candidate genes

An international research team led by the Central Institute of Mental Health (CIMH) in Mannheim/Germany has now conducted the largest genome-wide association study (GWAS) on borderline personality disorder to date. The analysis includes genetic data from around 13,000 affected persons and over 1.1 million control persons from a total of 14 countries. The aim was to identify genetic risk factors for the disorder and to better understand which biological mechanisms play a role.

The scientists analyzed millions of genetic variants (so-called SNPs) in the genetic material of the participants and were able to identify 11 independent genomic regions (loci) that are associated with an increased risk of BPD. Further analyses also identified nine specific genes that may contribute directly to the development of the disease.

Genetic proportion and predictive power

The proportion of susceptibility to the disease attributable to the studied genetic factors examined was estimated at 17.3 percent. Using a polygenic score (PGS) based on the results, the individual risk of developing the disease was predicted to be 4.6 percent on the same scale. “In our analysis, we were able to identify several new risk genes for BPD – an important step towards a deeper understanding of the genetic architecture of this complex disease. The results clearly show that borderline personality disorder, like other mental illnesses, has a polygenic basis,” says Dr. Stephanie Witt, Assistant head of the Department of Genetic Epidemiology in Psychiatry at the CIMH and last author of the study.

Broad overlap with other diseases

The study also shows that genetic risk factors for BPD have significant overlaps with other mental and physical illnesses. Particularly strong genetic similarities were found with post-traumatic stress disorder (PTSD), depression, ADHD, antisocial behavior, as well as suicidal and self-injurious behavior. Genetic overlaps were also found with physical illnesses such as chronic obstructive pulmonary disease (COPD) and diabetes.

These findings underline the fact that borderline personality disorder is a highly complex, polygenic disorder whose genetic basis is linked to both other psychiatric and somatic diseases. “Borderline personality disorder is one of the most serious mental illnesses – and yet we know surprisingly little about its biological basis. Our study shows for the first time at a genetic level that BPD is associated with a variety of other psychiatric and physical illnesses. This opens up new ways to better understand the causes and, in the long term, to improve the care of those affected,” says Dr. Fabian Streit, a member of the Hector Institute for Artificial Intelligence in Psychiatry (HITKIP) at the CIMH and lead author of the study.

“These findings highlight the highly polygenic nature of borderline personality disorder. They resemble the early schizophrenia GWAS results around 15 years ago, which initially identified only a few risk loci – before international collaborations and ever-larger cohorts led to an exponential growth of discoveries. A similar trajectory can be expected for borderline. It will therefore be crucial to extend studies to more diverse ancestry groups and to integrate genetic findings with clinical phenotypes and environmental exposures, such as trauma. Only through such efforts can we disentangle the underlying mechanisms and ultimately inform the development of targeted therapeutic strategies,” says Prof. Dr. Stephan Ripke, Head of the Laboratory for Statistical Genetics at the Department of Psychiatry and Psychotherapy at Charité – Universitätsmedizin Berlin and last author of the study.

Prof. Dr. Christian Schmahl, Medical Director of the Clinic for Psychosomatics and Psychotherapeutic Medicine at the CIMH, adds: “The new study provides important impetus for a better understanding of the biological causes and the resulting treatment options. The results fit very well with our increasingly transdiagnostic approach and underline the fact that we tailor our treatment plans to comorbidities.”

Large data sets and more diverse ancestry

The research team sees considerable potential in additional, larger data sets and in the inclusion of diverse ancestry groups. More differentiated phenotyping and dynamic omics measures such as epigenomic and transcriptomic should also help to better understand genetic risks in combination with environmental influences such as traumatic experiences.

The researchers make their results available to the scientific community. The data should facilitate follow-up work and benefit patients in the long term. Studies show that drugs with genetic support are more likely to be successful in clinical trials.

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Fabian Streit is supported by a 2023 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation with support from the Families for Borderline Personality Disorder Research.

About CIMH
The Central Institute of Mental Health (CIMH) stands for internationally outstanding research and pioneering treatment concepts in psychiatry and psychotherapy, child and adolescent psychiatry, psychosomatics and addiction medicine. The CIMH clinics provide psychiatric care for the population of Mannheim. At the CIMH, mentally ill people of all ages can rely on the most advanced treatments based on international standards of knowledge. Educating people about mental illness, creating understanding for those affected and strengthening prevention is another important part of our work. In psychiatric research, the CIMH is one of the leading institutions in Europe. Since 2021, it has been a site of the German Centre for Mental Health. The CIMH is institutionally linked to the University of Heidelberg through jointly appointed professors from the Mannheim Medical Faculty. The CIMH is a member of the Health + Life Science Alliance Heidelberg Mannheim.