Information for Clinicians
Psychiatric and neurodevelopmental disorders result from both genetic and environmental factors. We know that the role of genetics, or the heritability, of these disorders is considerable although it varies from disorder to disorder. Heritability refers to how much of the trait can be explained by genetic factors (as opposed to environmental factors). For example, autism spectrum disorder and schizophrenia are highly heritable (i.e., genetics play an influential role), whereas the heritability of disorders, such as major depressive disorder, are considerably lower (i.e., genetics play less of a role). Genetic factors do not cause psychiatric disorders per se but can increase a person's risk of developing the disorder. Psychiatric and neurodevelopmental disorders are polygenic, which means that many genes act together to increase a person's risk for a disorder. This is similar to traits like height. There is no one gene for depression, anxiety, autism spectrum disorder, or any other disorder but many hundreds of thousands of variants that contribute to risk.
Types of Genetic Variation
The genome is a like book made up of 3 billion pairs of letters. We get one set of letters from our mothers and one set from our fathers. For any given pair , the type of letters can vary from person to person. If the letters in that pair exist in at least 5% of people are considered common (single nucleotide polymorphism - SNP) and those that are present in <1% of people are considered rare single nucleotide variants (SNVs). Another type of rare genetic variation are copy number variants (CNVs) which are also segments of the genome (the size of words, paragraphs or pages of the genome book) that can be deleted or duplicated.
Common Variation (SNPs)
Individually, common SNPs can increase a person's risk of developing a disorder by a small amount, but collectively SNPs can increase disorder risk more substantially. This combined risk of many SNPs or ‘polygenic risk scores’ are calculated by adding together an individual’s SNPs weighted by their effect sizes (or how much they contribute risk) for a given disorder, and provide an overall picture of an individual’s disorder risk coming from common genetic variation.
The hope is that in the future polygenic risk scores will be brought to the clinic and could be used in a number of ways. Examples include:
- Helping to predict which individuals will develop a psychiatric disorder (risk prediction)
- Identifying which specific diagnoses a person has and what diagnoses they do not have (differential diagnosis)
- Their possible illness trajectories and outcomes (prognosis)
- How these individuals might respond to medication or therapy (treatment response)
Polygenic risk scores for psychiatric conditions are NOT yet ready to be used in any of these ways in the clinic. In order to be clinically useful, polygenic scores would need to show high levels of accuracy in predicting psychiatric conditions like depression or schizophrenia, and give us meaningful information beyond risk factors that can already be measured in the clinic. In the future, as polygenic scores become more powerful, they could be used in genetic counselling of individuals with extreme scores (i.e. very high or very low).
Useful references:
Polygenic risk scores: from research tools to clinical instruments
Polygenic risk scores in psychiatry: Will they be useful for clinicians?
Rare Variation
SNVs and CNVs can increase the risk of disorders on the neurodevelopmental spectrum, including intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder and schizophrenia, and have far larger effects than individual common variants. Testing for CNVs is widely available in medical genetics laboratories for specific indications, usually including neurodevelopmental phenotypes. Testing for SNVs is less commonly carried out but likely to increase as clinical laboratories carry out more sequencing.