Genetic influence on psychiatric diseases: A “risky” business
Most of us are aware that why we differ from each other in multiple aspects is because we have different gene pools Each of us possess two copies (alleles) for each gene, one from each parent. Now, these genes can also be a contributing factor towards the development of many disorders. Polygenic disorders are conditions that are caused by the interaction of multiple genes, and are also affected by environmental factors (diet, exercise, lifestyle etc.), that are not directly controlled by our genes. Most common complex diseases, like cancer, schizophrenia, type 2 diabetes fall under the umbrella of polygenic disorders. Given that a multitude of factors is involved in the development of these disorders, it is important to have an approach to accurately identify individuals at risk. And, this is where polygenic risk scores can be of help.
Polygenic risk scores and environmental factors contributing to the development of coronary artery disease (Adapted from Aragam and Natarajan, 2020)
Polygenic risk scores (PRS) aid in the prediction of genetic predisposition of individuals to diseases. How this happens is that all of us carry risk variants for all diseases, but since these diseases are governed by multiple genes, it is the cumulative burden of the risk variants that determines the susceptibility of an individual towards a disease. The risk variants and their associated weights can be assessed by genome wide association studies (GWAS). PRS for various diseases can be determined from pretty much any biological sample, such as saliva or blood. Though the sample is collected only once, the PRS can be updated depending on the identification of new risk variants by scientific community later in the future. A risk variant is an allele that appears significantly more frequently in disease cases than in healthy controls. The PRS is then a metric that adds up individually associated single nucleotide polymorphisms (SNPs) listing risk alleles obtained from a GWAS.
PRS can be employed in predicting associated risk of individuals for multiple disorders. Since complex polygenic diseases are governed by both genetic and environmental factors, the presence of a high PRS does not necessarily mean that the individual will develop the disease. However, the information of the risk can help clinicians to recommend preventive measures for at risk individuals, thus, minimizing the likelihood of disease development. The aim here is to use PRS along with other risk indicators to increase the accuracy of risk prediction and to improve disease management in the long term.
People with family history for a disorder may or may not present with high PRS due to multiple reasons. The person may have lesser risk variants than affected family members, the PRS also does not cover all risk variants. Also, non-genetic (environmental) factors also contribute to disease. Due to the non-linear nature of genetic contribution to disease development, many individuals who have a high PRS might not have any affected family members.
Nevertheless, PRS can provide relevant information on risk association for complex disorders that possess a genetic contribution. Psychiatric disorders are known to have an underlying genetic component alongside environmental factors. Hence, PRS can be a useful tool in psychiatry, helping clinicians make informed decisions and provide early intervention in symptomatic individuals.
In a general population setup, the information on PRS could help stratify the population and identify at risk individuals for further evaluation, aiding in an earlier diagnosis. Most psychiatric disorders like schizophrenia, bipolar disorder manifest similar early symptoms, mainly depression and anxiety. The knowledge of PRS can help distinguish individuals with a higher burden of the disease and provide early intervention.
With further advancements in predictions of risk variants and their possible effects, it might be possible to determine the effect a particular medication might have on an individual, thus aiding in providing targeted treatment. Check out episode 8 of the podcast to know more. Link: https://www.pmedcast.com/2020/03/25/episode-008-dr-maryna-polyakova-ai-depression-treatment/
It is true that PRS can be immensely useful in risk prediction for complex psychiatric disorders, however, it is important to reiterate that PRS alone is not sufficient, as multiple factors are at play in disease development. It is very important to train clinicians to disseminate the information of PRS in a clear and coherent manner to individuals so as to not cause a state of panic in the person. It is important that clinicians are equipped to understand and analyze the PRS along with other factors like family history, visible symptoms, to make an informed decision regarding further interventions.
Improving the accuracy of the PRS requires identification of new risk variants, thus improving the predictions. So far, most GWAS studies are conducted in people from European ancestry, it would be important to also include samples from people of other underrepresented ancestries, which might modify the PRS and enhance accuracy. It is also important to foster collaborations between researchers and clinicians so that dissemination of new and relevant information is accelerated.
To get more information on PRS and its utility in clinical psychiatry, tune in to Episode 19 of the Personalized Medicine Podcast where Professor Naomi Wray (Episode link- https://www.pmedcast.com/2020/11/11/e019/), from the Institute for Molecular Science and Queensland Brain Institute at the University of Queensland, gives us a deep dive into PRS and its application in psychiatry.
References:
Aragam, K.G., and Natarajan, P. (2020). Polygenic Scores to Assess Atherosclerotic Cardiovascular Disease Risk: Clinical Perspectives and Basic Implications. Circ. Res. 1159–1177.
Andlauer, T.F.M., and Nöthen, M.M. (2020). Polygenic scores for psychiatric disease: From research tool to clinical application. Medizinische Genet. 32, 39–45.
Murray, G.K., Lin, T., Austin, J., McGrath, J.J., Hickie, I.B., and Wray, N.R. (2021). Could Polygenic Risk Scores Be Useful in Psychiatry?: A Review. JAMA Psychiatry 78, 210–219.
Wray, N.R., Lin, T., Austin, J., McGrath, J.J., Hickie, I.B., Murray, G.K., and Visscher, P.M. (2021). From Basic Science to Clinical Application of Polygenic Risk Scores: A Primer. JAMA Psychiatry 78, 101–109.
