Informing precision psychiatry through developing comprehensive genomic models of mental health disorders

Severe mental illness dramatically impacts the wellbeing of affected individuals and their families and are a leading cause of disability worldwide. In the UK alone, around 13.5 million people are affected by mental illness each year, which places a significant burden on the economy through direct (health care) and indirect (lost work and productivity) costs. Current treatments for severe mental illness, such as schizophrenia, have limited efficacy. To improve patient outcomes, there is an urgent need to develop more effective treatments in psychiatry, as well as approaches to target treatments to individuals who are most likely to benefit from them. While the exact causes of severe mental illness are unknown, a wide body of research has demonstrated an important role for genetic factors. For example, common and rare genetic variants spread across many different genes have been identified as risk factors for schizophrenia. However, no individual genetic cause is by itself necessary or sufficient for the development of schizophrenia. Moreover, different combinations of risk factors are observed in individuals with the same psychiatric diagnosis, and some genetic factors are shared across different mental health conditions. This complexity has made it challenging to translate genomic discoveries in conditions such as schizophrenia to improvements in patient care. During the renewal phase of my Fellowship, I will leverage new genomic resources to enhance our understanding of the genetic basis of severe mental illness. I will focus on two key research areas that build directly on findings from the first phase of my Fellowship. The first aims to identify genetic links to specific clinical features and treatment outcomes in individuals diagnosed with schizophrenia, bipolar disorder or severe depression. This research is needed because symptoms vary widely among individuals with a particular mental illness, and individuals with the same disorder do not always respond to the same treatments. By understanding how genetic factors contribute to this variation, we can uncover the biological causes of these symptoms, which in turn, may lead to the development of more effective treatments. Moreover, discovering genetic factors that influence treatment outcomes can inform approaches aiming to identify patient groups more likely to benefit from specific treatments. Finally, I will examine whether genetic variants that are already known to increase risk for schizophrenia have effects on other medical outcomes, such as diabetes, hypertension or renal failure, which will help clinicians in planning and managing the care of people with these mutations. The second area of research aims to address gaps in our understanding about the utility of DNA sequencing for detecting clinically relevant mutations in individuals with severe mental illness. Confirming a genetic contribution to a patient's condition can be beneficial, particularly in terms of genetic counselling. To better understand the role of genetic testing in mental illness, it is important to determine the proportion of patients carrying a clinically relevant mutation. I will conduct the largest sequencing study to date examining the rates of clinically relevant mutations in severe mental illness. I will also investigate whether individuals with a severe mental illness and a co-occurring medical condition, like developmental delay, are more likely to carry clinically relevant mutations. This information will help identify which patient groups should be prioritised for genetic testing. The long-term goal of my Fellowship is to advance precision medicine in psychiatry. I will work with selected partners from industry and the NHS to accelerate this process and ensure that my findings contribute to improvements in clinical care for individuals with severe mental illness.