A transdiagnostic approach drives new therapies in psychiatry for various disorders

A massive international study including more than one million cases, published in Nature Genetics, analyzes the most comprehensive genetic map to date of 14 of the most prevalent psychiatric disorders. This map quantifies a reality that psychiatrists around the world have long observed in clinical practice: psychiatric disorders are deeply interconnected, not only clinically but also genetically, which greatly complicates differential diagnosis.

The study groups the 14 disorders into five families based on genetic criteria. All share, to a greater or lesser extent, genetic risk markers, but these overlaps are stronger within the same group. For example, anxiety shares more markers with other disorders in the fourth group (internalizing disorders), such as depression and post-traumatic stress disorder, but also with anorexia nervosa and obsessive-compulsive disorder (OCD) in the first group (compulsive disorders). This creates a network of cross-disorder genetic relationships, demonstrating the need for a transdiagnostic approach to better understand and treat them.

The paper is a joint effort involving Vall d’Hebron University Hospital, the Vall d’Hebron Research Institute (VHIR), the Bellvitge Biomedical Research Institute (IDIBELL), Bellvitge University Hospital, Sant Joan de Déu Hospital, the Sant Joan de Déu Research Institute, and the Sant Pau Private Foundation, as well as the Autonomous University of Barcelona and the University of Barcelona. Three groups from the Spanish Biomedical Research Networking Center (CIBER-SAM, CIBER-ER and CIBER-OBN) and the University of Santiago de Compostela also participated.

“This study represents a highly significant paradigm shift for psychiatry, as it confirms with large-scale data that diagnostic boundaries are much more blurred than classical manuals suggest. We have shown that disorders are not watertight compartments; rather, there are gradients of shared genetic risk across seemingly distinct pathologies,” explains Dr. Josep Antoni Ramos-Quiroga. “This evidence compels us to move toward dimensional models that better reflect biological reality, allowing us to move beyond traditional diagnostic models and focus on a transdiagnostic approach targeting shared biological mechanisms.”

This work began by analyzing biological factors and comparing them, classifying them into five groups based on genetic similarity. As a result, disorders associated with risk markers were clustered into families with high genetic overlap. Closely related pairs include anorexia nervosa and OCD, ADHD and autism, and depression and post-traumatic stress disorder. The strongest relationship was observed between schizophrenia and bipolar disorder, which could almost be considered genetically twin conditions.

Genetics is only one piece of the puzzle

When discussing shared genetic risk among disorders, it is important to remember that genetics is not the only piece of the puzzle. It accounts for only a percentage of the risk of developing a psychiatric disorder, varying by condition and individual case.

For example, in eating disorders, genetics accounts for around 45% of the risk. The remaining 55% is determined by environmental factors, and often, despite genetic vulnerability, an environmental trigger is required to develop the illness. In other disorders, genetics plays a greater role (such as in schizophrenia or bipolar disorder) or a smaller one (such as in anxiety disorders). Environmental influences, personal experiences, and social context play a decisive role in whether this predisposition ultimately manifests.

“Genetics helps us understand vulnerability, but it does not determine an inevitable fate. The value of these findings is that they will allow us to identify common biological targets and potentially develop treatments that benefit different disorders sharing the same molecular basis,” says Dr. Marta Ribasés.

15 years of an international project that continues

This milestone in psychiatry comes after 15 years of data collection and analysis by the Psychiatric Genomics Consortium, an international consortium involving more than 800 researchers worldwide aiming to describe the genetic architecture of psychiatric disorders in order to apply this knowledge in clinical practice.

“We are facing a paradigm shift. Integrating genetics with clinical and environmental data brings us closer to precision psychiatry, where treatment is based not only on a diagnostic label but on each person’s biological and clinical profile,” concludes Dr. Ribasés.