WHAT ARE THE CAUSES OF PSYCHOSIS?
Psychotic disorders including schizophrenia and bipolar disorder are potentially severe conditions affecting about 3% of the population, and constitute a major economic challenge throughout the world. A range of effective antipsychotic medications and psychological therapies are available, but about one in every three patients do not benefit from them. Antipsychotics can cause a range of common and serious side effects such as sleepiness, shaking, sexual dysfunction, obesity and diabetes.

Psychotic disorders emerge because of environmental as well as genetic factors. Established environmental risks include pregnancy and birth complications affecting a baby's brain development, the use of cannabis (especially if starting young), migration, growing up in a city and other factors. However, psychosis also runs in families and genetic factors (we will refer to them as "genetic variants") are important. There are many genetic variants, which are common in the population, but only convey small increases in risk for the disease. We know there are also a few genetic variants that are very rare (found only in 1 or 2 of every 1000 people), but when present, the risk of developing schizophrenia is increased between two and thirty-fold. Some of these rare genetic variants also increase the risk for learning disabilities, autism, epilepsy and a range of physical health problems. These rare genetic variants constitute the strongest known risk factors for schizophrenia and are the focus of this project.

STUDY OBJECTIVES
1. Investigate the influence that these rare high-risk genetic variants have on brain function and structure.
2. Understand why some carriers of the same high-risk variant develop different neurological or mental disorders and why some carriers remain well. Explore how other genetic as well as environmental factors modulate the impact of the high-risk variants: Can any of them reduce risks?
3. Investigate genetic and environmental influences on response to antipsychotic medications.
4. Combine or compare data from ALSPAC with our study at University College London (UCL).

HOW WILL WE DO THE RESEARCH?
We will analyse a large sample of volunteers who participated in our study in UCL including people with schizophrenia, bipolar or other psychotic disorders and controls without these conditions. More than 14,000 participants have already had their DNA examined with the latest genetic technology. Many study participants have completed brain scans, electroencephalograms (EEG tests similar to those used in epilepsy), cognitive and clinical assessments. To our knowledge, this is one of the largest and most thoroughly characterised studies of biomarkers and genetics of psychosis.

The ALSPAC project is similar to our study in London. Because some of the genetic variants we are investigating are very uncommon, it is best to combine the two studies and analyse them together. Where the genetic variants and traits are common and we have large samples already, then we will compare the findings from our study and from ALSPAC. This approach (combine or compare information) enhances the accuracy of the research.

WHY IS THIS IMPORTANT?
This project will offer new insights into how genetic variants predisposing to schizophrenia can influence brain anatomy, physiology and cognitive abilities. A better understanding of the genetics of psychosis will provide leads for the development of new medications and psychological interventions. Genetic advances will also help to identify people at high risk of developing psychosis who will benefit from earlier access to treatments, leading to a better recovery.