A large study of people whose traits or health outcomes do not match expectations based on their genetic risk score has found that the disparity can often be explained by rare genetic variants.
The study was carried out by researchers from the Big Data Institute at the Nuffield Department of Population Health and the Department of Statistics, University of Oxford and is published in The American Journal of Human Genetics.
Scientists are increasingly using polygenic scores, which combine the effects of many common genetic variants, to predict traits like height and BMI (body mass index) as well as risk of diseases such as diabetes and heart disease. But while most people have traits and conditions that align with their polygenic score, some do not.
These so-called ‘misaligned’ individuals were the focus of the study. Among 400,000 individuals in the UK Biobank, the researchers identified a small subset whose physical characteristics were substantially different from those forecast by their polygenic score. They found that such individuals often carry rare, high-impact variants in genes linked with severe genetic disorders.
For example, someone who was taller or shorter than expected, often had rare variants in genes linked with growth disorders, while someone with higher or lower than expected LDL cholesterol often had variants associated with extreme lipid disorders. The researchers looked at rare variants associated with several other traits including bone density and age at menopause.