Biomarkers to investigate Genetics, Environment and Mechanisms in Schizophrenia (Bio-GEMS).

Bio-GEMS: BIOMARKERS TO INVESTIGATE GENETICS, ENVIRONMENT & MECHANISMS in SCHIZOPHRENIA

WHAT ARE THE CAUSES OF PSYCHOSIS?
Psychosis, including schizophrenia and bipolar disorder, affect about 3% of the population; they create major social and economic costs throughout the world. Effective medications and psychological therapies are available, however, one in three patients do not respond to them. Furthermore, antipsychotic drugs have common side effects, which contribute to many people stopping their medication and relapsing. Side effects can range from drowsiness to shaking, sexual dysfunction, and obesity.

Psychotic disorders emerge from both 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 childhood trauma. However, psychosis also runs in families and genetic factors are important, we refer to these as "genetic variants". There are hundreds of genetic variants, which are common in the population, but only convey small increases in risk for psychosis. We also know of a few genetic variants that are very rare, 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 other health problems. Some people carry these high-risk genetic variants, yet they stay healthy, and the origin of their resilience remains a mystery.

Despite breakthroughs in our understanding of the causes of psychosis, we have limited knowledge on how genetic risk or resilience come about. We intend to use state of the art biomarkers of brain function to investigate cognitive and perception processes that are key in psychotic disorders. Psychological or EEG tests and MRI scans are safe and optimally designed to achieve this.

OBJECTIVES
1. Investigate the influence of high-risk genetic variants on brain development and function.
2. Understand why some carriers of the same high-risk variant develop different neurological or mental disorders and identify genetic sources of resilience.
3. Investigate if people who carry high-risk genetic variants are more likely to go on to experience adverse environmental factors, which further increase schizophrenia risk.
4. Combine or compare our data with other projects in large international studies.

HOW WILL WE DO THE RESEARCH?
We will analyse a large sample of volunteers who already participated in our study including people with schizophrenia, bipolar or other psychotic disorders and controls without these conditions. More than 14,000 participants have already donated a DNA sample. Many of them have also completed brain scans, electroencephalograms (EEG tests like those used in epilepsy), cognitive and clinical assessments. We will invite another 3,000 individuals, to take part in the project. All samples will be tested with the latest genomics technology. To our knowledge, Bio-GEMS is one of the largest and most thorough studies in psychosis.

WHY IS THIS IMPORTANT?
Bio-GEMS will provide new insights into how genetic variants influence brain anatomy, physiology, and cognitive development. Understanding the genetics of psychosis, is essential to develop 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.

BIO-GEMS
Recent studies have identified 270 common loci associated with schizophrenia (SWGPGC et al, 2020) as well as copy number and single nucleotide genetic variants (CNVs/SNVs) with large odds ratios for schizophrenia (Marshall et al, 2017; Singh et al, in press). However, we have limited understanding of their mechanisms.

AIMS
1. Characterise the effects of high-risk (CNVs/SNVs) and other genetic variants on biomarkers of brain function and structure.
2. Investigate high-risk and other variant influences on clinical outcomes.
3. Investigate associations between high-risk variants and environmental risk factors for schizophrenia.
4. Conduct joint analyses and independent replications.

METHODS
OUR EXISTING SAMPLE: 14,000 people with psychosis and controls genotyped with SNP-microarrays. Whole genome/exome sequencing are available for 6,700 of them. Most participants are characterised for cognitive, neuroimaging and EEG biomarkers. NEW DATA COLLECTION: Array genotyping for 3,000 participants, clinical assessments, and whole exome sequencing for 2,000 of them. A subgroup of 600 will undergo deep phenotyping with cognitive, EEG testing and biobanking.

1. Biomarker outcomes: Model the effects of CNVs/SNVs and polygenic scores on EEG, cognitive and MRI biomarkers.
2. Clinical outcomes: Model the effects of CNVs/SNVs and polygenic scores on clinical outcomes.
3. Environmental outcomes: Models to test if high-risk variants are associated with subsequent exposure to schizophrenia environmental risk factors (obstetric complications, cannabis use, Maudsley environmental risk score).
4. Replication/joint analyses in collaboration with compatible studies: UK Biobank (500,000 people), The 100,000 Genomes Project (UK clinical sample), iPSYCH (130,000 Danes with/without mental disorders), ALSPAC (14,000 Welsh cohort), and deCODE (Icelandic population).

UNDERSTANDING BIOLOGICAL MECHANISMS IS KEY TO DEVELOP NEW TREATMENTS FOR PSYCHOSIS.