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Approved research

Validity and performance of inherited risk assessment for common diseases using polygenic risk score, family history, and high-penetrance genes

Principal Investigator: Dr Jianfeng Xu
Approved Research ID: 50295
Approval date: August 1st 2019

Lay summary

Past research has shown that certain single neucleotide polymorphisms (SNPs) are associated with increased risk of developing a wide range of diseases. In an effort to assess the cumulative effect of these risk-associated SNPs on disease development, different methods in different stages of translation have been devised to measure this risk, called polygenic risk scores (PRS). While most of these methods of calculating PRS have shown to be valid in the broad sense (higher percentiles of PRS are associated with higher disease risk), none have been validated in the narrow sense (calibration of polygenic risk scores with observed risk). NorthShore has developed a PRS method called the Genetic Risk Score (GRS), which calculates disease risk from known disease risk-associated SNPs for a wide variety of diseases, such as prostate cancer, colorectal cancer, and Alzheimer's disease. The GRS differs from other PRSs in that it is easier to calculate and understand because its scores can be simply interpreted as relative risk to the general population (due to being population standardized). We plan to utilize the large number of subjects available through the UK Biobank to assess both the broad and narrow sense validity of GRS for many diseases and establish that GRS can supplement family history and high penetrance genes for evaluating disease risk. This will be on ongoing project with continual assessment of GRS validity for many diseases. The current proposal will provide critical value in evaluating whether GRS is valid for individual risk assessment and add value the current risk assessment standard of care (family history and high penetrance genes). If GRS is shown valid for individual risk assessment, it has the potential to identify many more at-risk individuals than family history and high penetrance genes alone, which can lead to more targeted disease screening and personalized treatment plans.