Identifying actionable resilience factors for mental health leveraging prospective cohorts and novel biostatistical tools

Mental disorders are characterized by the fact that they affect thoughts, feelings, behavior and relationships. Mental disorders have a genetic predisposition that can increase vulnerability (inheritance) and, together with external stresses (environment), contribute to illness. Based on the discovery of rare gene variants that confer protection (resistance) against genetic diseases, we investigated whether there are inherited or genetic variants that promote resistance to inherited polygenic disorders such as schizophrenia. An important factor for prevention is to examine phenomena across diagnostic categories, and mental disorders have a number of common characteristics. Psychosis, i.e. thought disorders, sensory illusions or delusions, is found in schizophrenia, but also in bipolar disorder and severe depression. We see the same with mood disorders, which are the main characteristics of depression and bipolar disorder, but it can also occur in psychoses. All types of disorders often have anxiety and substance abuse. It is therefore important to study such psychological phenomena across diagnoses. Genetic differences between individuals provide the biological basis from which mental disorders develop. But mental disorders are not caused by a single gene. Instead, it is now understood that disorders such as depression and schizophrenia are driven by hundreds of genetic variants in a complex interaction with environmental factors. The project has identified several of the genetic components of mental disorders and several studies that provided new insight into the genetic basis of mental disorders. We found that genetic variants associated with a particular mental disorder are highly likely to influence other mental disorders. Interestingly, these genetic variants also affect human characteristics such as cognition and personality. This indicates that the majority of "genes for depression" are also "genes for cognition" and "genes for personality". The findings of genetic overlap have important implications for how we interpret genetic discoveries, define mental disorders and design future aids for the follow-up of people with mental disorders that can contribute to improving their treatment and prevention. The analyses showed that many genetic variants overlapped across disorders. This means that genetic variants that affect the risk of getting a mental disorder are very likely to also affect the risk of getting another disorder. Surprisingly, there was also a similar pattern of extensive genetic overlap with cognition and personality, indicating that most genetic variants related to mental disorders were also associated with variants for cognition and personality traits such as neuroticism. We have leveraged existing GWAS data and utilizing well-characterized clinical schizophrenia and bipolar disorders samples from hospitals sample integrated with large population samples from biobank material with registry and health surveys information, and collaborate with large Scandinavian samples. We have applied our novel biostatistical and bioinformatics approaches, and improved them for mental disorders, as we have during the project progress learned more about the genetic architecture of psychiatric disorders and traits.

The "ResilieMent" project applied a comprehensive and integrated analysis of data from a combination of methods and unique population biobank and clinical samples. The findings have opened new horizons in our understanding of the resilience factors in mental illness. The project has developed novel analytical methods for psychiatric genetics which can also be applied to other complex human diseases, which are major health challenges today. We have identifying the underlying disease risk and protective factors for severe mental disorders (schizophrenia, bipolar disorders). This can be further developed, and lead to major health benefits through the development of new treatment and prevention regimens. The results can form the basis for new intervention that can reduce social inequalities and better prevention and treatment for patients with severe mental disorders, including bipolar disorders and schizophrenia. The project has led to innovations and the analytical tools can be taken further to be developed into health data products and improved tools for health care personnel for better treatment and which can result in product development.

Mental illnesses, including affective and psychotic disorders, are leading global causes of morbidity and among the most costly human disorders. Identifying the underlying pathophysiology is imperative and can lead to major health benefits, through better treatment and prevention strategies. The heritability is high, and recent discoveries of polygenic risk factors in schizophrenia and bipolar disorders have enabled us to identify environmental factors that interact with genetic susceptibility during the critical phase of adolescence and early adulthood. The current project combines novel analytical tools with genotypes from Norwegian biobanks and data from health registries and hospital samples, to identify resilience factors in severe mental disorders. This can form the basis of public health efforts to target actionable environmental factors, to reduce the risk of disease development. We will obtain genotypes from approx n=300000 including the MoBa birth cohort, which has key information about early environmental factors (pregnancy, neonatal and childhood/adolescence). This will form the basis for studies of environment interactions with genetic risk/protective factors, obtained from international psychiatric genetics consortia with one million samples. We will apply novel Bayesian statistical tools for polygenic phenotypes to identify interacting environmental risk/protective factors, and replicate in samples from Nordic partners, building on the similarities in genetic background, culture and health care systems. The project is based on collaboration between universities, hospitals, the Institute of Public Health, and industry. The project builds on a tight collaboration between Nordic research groups, which are leaders in genetics of mental illness, and US partners with frontline expertise in bioinformatics and biostatistics, leading to synergy. The project will provide key knowledge about actionable public health factors with potential high societal gain.