Molecular Genetic Studies of Schizophrenia: Understanding Treatment Resistance and Outcomes to Inform Precision Psychiatry.

Schizophrenia (SZ) is a severe psychiatric disorder that has a profound impact on the individual and society. Over half of people with SZ have long-term psychiatric problems, 80-90% are unemployed, and life expectancy is reduced by 10-20 years. These outcomes have not changed over recent decades. Current antipsychotic treatment often causes major adverse effects and is not effective in treating symptoms in around 30% of those with SZ (termed treatment resistant SZ - TRS). Developing more effective and acceptable treatments for SZ is a priority for patients but has proven a major challenge for researchers given we know little about the biological processes that cause the condition, and even less about what influences good or bad outcomes, response to existing treatments, and we do not have established ways of identifying specific groups of people with SZ that may benefit from different treatment approaches.

Precision medicine seeks to address these issues with the aim of developing more targeted treatments, minimising adverse effects and improving patient outcomes. In other areas of medicine, genetics has been central to the success of precision medicine. We have led international research over the last decade that has confirmed the important contribution genetics makes to SZ risk. In this programme we will use this experience, and apply modern genetic tools, to advance precision medicine approaches in psychosis and SZ by investigating the genetic basis of TRS and wider patient outcomes.

We have designed the research programme in consultation with patients who have lived experience of psychosis, and informed by these discussions, we will focus our projects on TRS and other outcomes prioritised by patients including (minimising) hospitalisation and relationship and occupational functioning. We have shown that genetics contributes to whether symptoms respond to treatment, and we will now identify both common and rare genetic variants (risk alleles) that are associated with TRS and the other outcomes.

We require very large datasets to address these aims so we will bring together a consortium of international researchers and genetic and clinical data from 103,478 research participants. We will use these risk alleles to identify genes associated with treatment outcomes and will analyse them with other biological datasets to gain insights into the biological processes involved in these treatment outcomes. In addition, we will conduct analyses to identify existing medications that may impact TRS and alter outcomes.

The potential impact of precision medicine is likely to be greatest if it is possible to differentiate between those who need new or more intensive early interventions and those who are expected to do well with existing interventions. Genetic risk scores represent the total amount, or sometimes the particular patterns, of genetic variants that influence a condition, or any other partly heritable characteristic, that a person carries. In other common illness, genetic risk scores are starting to be helpful in predicting course, outcomes, and the need for particular treatments. We aim to see if genetic risk scores based on the DNA variants that influence outcome can be used to predict those outcomes in people with schizophrenia, to influence TRS and outcomes in SZ.

We believe completion of these aims will deliver important insights into the feasibility of precision medicine in SZ and will enhance our understanding of the fundamental biology of TRS and patient outcomes in SZ, highlighting potential novel treatment targets and identifying separate groups of people with psychosis and SZ who would benefit from different therapeutic approaches.

Our aim is to exploit genomics in ways that will most rapidly impact on clinical care and help realise the potential of precision psychiatry for schizophrenia (SZ). Rather than focussing on further genomic studies of SZ per se, we will take a novel approach and focus on the genomics of treatment resistance and wider patient outcomes, which are highly heterogeneous. This is justified because many effective treatments in medicine are targeted at modifying progression and outcomes rather than reversing basic aetiology, and therefore genes that influence progression and outcome are more likely to implicate potential therapeutic targets than those that influence disease onset. These considerations may be especially salient for a neurodevelopmental disorder such as SZ, where at least some of the basic pathophysiological processes likely occur 20 years or more before onset. We propose to undertake a programme of co-ordinated and related projects to illuminate the genetic architecture (common and rare variant), identify causal variants, genes, and biological process that underpin variation in treatment response/resistance and other outcomes in schizophrenia. We will also exploit the findings to develop genetic predictors of outcomes and treatment resistance based on all classes of genomic variant. We will also investigate the contributions made by classes of variant that are best identified by whole genome sequencing, including certain types of structural variant and repetitive elements. Our study will be based on existing phenotypic and genomic from up to 103,478 cases assembled by ourselves and collaborators. We expect to deliver fundamental insights into the biology of outcomes in schizophrenia, provide resources for stratifying patients and predicting outcomes, suggest novel therapeutic targets, and make a major contribution to the journey towards precision medicine in psychiatry.