Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations

Abstract

A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.

Polygenic risk scores

“…PGRSs are also referred to as genome‐wide polygenic scores and genetic risk scores (Khera et al, ). A PGRS is a value that indicates the likelihood of an outcome developing due to a person's genome.…”

“…However, you can have a PGRS for any trait such as height, sporting ability, or mental ability (Plomin & van Stumm, 2). A PGRS accounts for all the genes known to influence a particular outcome and weights some of these according to how strongly they are known to be associated with that outcome (Khera et al, ). PRGSs have increased in popularity and in utility as they are becoming better.…”

“…In theory, there is no limit to what can be estimated using PGRSs but some specific examples of PGRSs for non‐communicable diseases (NCDs) including CHD, type‐2 diabetes, inflammatory disease and breast cancer exist (Khera et al, ). While the potential for a low‐cost method of indicating risk and providing health professionals with a useful starting point for individualized health promotion, PGRSs remain untested clinically (Knowles & Ashley, ).…”

Lifestyle and cancer incidence and mortality risk depending on family history of cancer in two prospective cohorts

“…Genome‐wide association studies (GWAS) have led to the discovery of a large number of low penetrant and common genetic variants which add to explaining familial risk . The clinical utility of using genetic testing and polygenic risk scores for population stratification has remained limited but may prove its usefulness in the near future . While the evidence for the effectiveness of using family history information in disease prevention is limited, subjects with a family history of disease may constitute an at‐risk group (either due to hereditary or environmental factors) and may be more motivated to take preventive actions to lower their risk.…”

47th European Mathematical Genetics Meeting (EMGM) 2019, Dublin, Ireland, April 8-9, 2019

“…While the heritability of lifespan itself is low (7-12%) [1], the many underlying age-related diseases and mortality risk factors each have genetic components that can be used to inform life expectancy. For example, individuals carrying many common deleterious variants for cardiovascular disease are more than three times as susceptible to the disease [2], and can therefore expect to have shorter lifespans on average. Here, we generate and test polygenic survival scores using >1 million parental lifespans from UK Biobank and other European cohorts.…”