Genome-wide association studies, Polygenic Risk Scores and Mendelian randomisation: an overview of common genetic...

Genetic information will be increasingly integrated into clinical eye care within the current generation of ophthalmologists. For monogenic diseases such as retinoblastoma, genetic studies have been relatively straightforward as these conditions result from pathogenic variants in a single gene resulting in large physiological effects. However, most eye diseases result from the cumulative effects of multiple genetic variants and environmental factors. In such diseases, because each variant usually has an individually small effect, genetic studies for complex diseases are comparatively more challenging. This article aims to provide an overview of three genetic epidemiology methods for polygenic (or complex) diseases: genome-wide association studies (GWAS), Polygenic Risk Scores (PRS) and Mendelian randomisation (MR). A GWAS systematically conducts association analyses of a trait of interest against millions of genetic variants, usually in the form of single nucleotide polymorphisms, across the genome. GWAS findings can then be used for PRS construction and MR analyses. To construct a PRS, the cumulative effect of many genetic variants associated with a trait from a prior GWAS is calculated and taken as a quantitative representation of an individual's genetic risk of a complex disease. MR studies analyse an outcome measure against the genetic variants of an exposure, and are particularly useful in investigating causal relations between two traits where randomised controlled trials are not possible or ethical. In addition to explaining the principles of these three genetic epidemiology concepts, this article provides a minimally technical description of their basic methodology that is accessible to the non-expert reader.