Schizophrenia is a common, complex, mental disorder, affecting 0.5–1% of the population. It mostly presents with several episodes and can become a chronic illness in many sufferers. It is characterized by disintegration of thought processes and of emotional responsiveness, most commonly manifesting as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is often accompanied by significant social or occupational dysfunction.

The CRESTAR team used genome-wide association analysis in a sample of over 11,000 patients with treatment resistant schizophrenia and almost 25,000 controls, to identify ten new genetic loci associated with treatment resistant schizophrenia, and clozapine treatment failure. We used epigenetic analysis (DNA methylation) to develop a model to predict clozapine use in schizophrenic patients, with good specificity and sensitivity. We assembled the largest known cohort of patients with agranulocytosis (544) and used these to identify new genetic risk loci for this rare but potentially serious side effects, including one gene (SPTA1) conferring a 15-fold increase in risk. We also searched for rare, high impact sequence variants associated by whole genome sequencing with the aim of uncovering variants useful for diagnostics. We also used polygenic risk score to show that the type 2 diabetes seen in patients on clozapine is mediated through weight gain, and that patients with a high polygenic risk score for schizophrenia were more likely to be receiving clozapine and be non-responders.