S.01.01 - Genetic influences in patient stratification and experimental medicine for brain disorders

Abstract

Schizophrenia, despite its complex aetiology, probably represents the least complicated picture for genetics in psychiatry, and we know more about it at the genetic level than most other psychiatric disorders. Here I will summarize the latest findings in schizophrenia genetics, and explore two questions: (1) what has genetics done so far to inform treatment? And (2) what might it do in the near future? When considering genetic risk, it is important to distinguish between common and rare genetic variants. Common genetic variants (e.g. single nucleotide polymorphisms, or SNPs) are implicated in disease risk through genome-wide association studies, or GWAS. The variants individually confer only a very tiny increased or decreased risk of the disorder, and they combine in an additive or 'polygenic' manner to significantly change an individual’s risk of disease. Rare variants that have been associated with schizophrenia confer a much higher risk of illness, and most are not usually seen in healthy individuals. They may, however, be found in individuals with developmental or intellectual disabilities, seizures disorders, or autistic spectrum disorders as well as people with schizophrenia. GWAS have implicated more than 100 genetic regions with schizophrenia. A recent study that includes Chinese individuals indicates that some risk loci are shared across ethnic/racial groups. Schizophrenia GWAS can be used to obtain a 'polygenic risk score', which is a score that can be generated for any individual for whom genome-wide SNP data is available. En masse, cases and controls differ significantly in their polygenic risk scores. However, the score cannot distinguish between cases and controls at the individual level. It may be useful for research purposes, but is not sensitive or specific enough for clinical risk prediction. The presence of a rare schizophrenia-associated genetic variant in the genome of a person with schizophrenia, however, can be considered to be the cause of the illness for clinical purposes. This may be useful for genetic counseling, and in some cases for individualizing treatment. The difficulty here is that there are likely to be many thousands of rare genetic variants in the population that confer a very strong risk of schizophrenia, and we have so far identified very few of them. Rare variants that have been identified to date are mostly copy number variants (CNVs), although a very large case-control exome sequencing study demonstrated that protein disrupting sequence variants in SETD1A can also cause schizophrenia. One promising method for identifying rare genetic variants that are responsible for schizophrenia in individual patients is 'diagnostic sequencing'. This involves sequencing the schizophrenia patient and, if possible, other family members, and trying to identify which genetic variants are 'unexpected', and therefore putatively pathogenic. This can be done by considering both the variant and the gene. At the variant level, pathogenic variants are likely to be rare in the population, and damaging to a protein. At the gene level, we can use population databases, such as ExAC and gnomAD, to identify which genes are often found to be damaged by variants in healthy people, and which genes are very rarely damaged in healthy people. Diagnostic sequencing is currently used for many other medical specialties and has a success rate of about 25-40%. This means that people with a suspected genetic disorder that doctors cannot easily identify with traditional methods can be diagnosed through analysis of their genomes (or exomes, which means just the coding regions of their genomes) about 25-40% of the time. Identifying a genetic cause for schizophrenia in this way may suggest an obvious treatment (e.g. resection of a pituitary tumour) or supplementation for metabolic disorders, which may help patients who are not responding to antipsychotics. Even if a genetic diagnosis does not suggest a novel treatment, it may guide the use of existing treatments, e.g. indicating that drugs that lower the seizure threshold or greatly increase the risk of obesity should be avoided if possible. I will conclude my lecture by presenting the latest results of a research study that my PhD student, Mitra Ameri, and I are carrying out to determine how often exome sequencing can lead to a clinically useful genetic diagnosis when applied to people who were diagnosed with a psychotic disorder before the age of 14. I will present data on the first 30 families, and discuss the very likely genetic diagnoses as well as variants of uncertain significance, and novel candidate genes. I will also demonstrate the importance of having sequence information for family members and population controls from all ancestral groups, especially those from Africa. In conclusion, schizophrenia is a highly genetic disorder and many cases are caused by single genetic variants that it is possible to identify through exome or genome sequencing and careful interpretation. This is becoming standard clinical practise for many disorders and may prove to be clinically beneficial for patients with psychiatric illnesses.