Validation of an Integrated Risk Tool, Including Polygenic Risk Score, for Atherosclerotic Cardiovascular Disease in Multiple Ethnicities and Ancestries.

The American College of Cardiology / American Heart Association pooled cohort equations tool (ASCVD-PCE) is currently recommended to assess 10-year risk for atherosclerotic cardiovascular disease (ASCVD). ASCVD-PCE does not currently include genetic risk factors. Polygenic risk scores (PRSs) have been shown to offer a powerful new approach to measuring genetic risk for common diseases, including ASCVD, and to enhance risk prediction when combined with ASCVD-PCE.

Integrated Polygenic Tool Substantially Enhances Coronary Artery Disease Prediction.

Background: There is considerable interest in whether genetic data can be used to improve standard cardiovascular disease risk calculators, as the latter are routinely used in clinical practice to manage preventative treatment.

Methods: Using the UK Biobank resource, we developed our own polygenic risk score for coronary artery disease (CAD). We used an additional 60 000 UK Biobank individuals to develop an integrated risk tool (IRT) that combined our polygenic risk score with established risk tools (either the American Heart Association/American College of Cardiology pooled cohort equations [PCE] or UK QRISK3), and we tested our IRT in an additional, independent set of 186 451 UK Biobank individuals.

Comprehensive Analysis of Constraint on the Spatial Distribution of Missense Variants in Human Protein Structures.

The spatial distribution of genetic variation within proteins is shaped by evolutionary constraint and provides insight into the functional importance of protein regions and the potential pathogenicity of protein alterations. Here, we comprehensively evaluate the 3D spatial patterns of human germline and somatic variation in 6,604 experimentally derived protein structures and 33,144 computationally derived homology models covering 77% of all human proteins. Using a systematic approach, we quantify differences in the spatial distributions of neutral germline variants, disease-causing germline variants, and recurrent somatic variants.

Three-dimensional spatial analysis of missense variants in RTEL1 identifies pathogenic variants in patients with Familial Interstitial Pneumonia.

Background: Next-generation sequencing of individuals with genetic diseases often detects candidate rare variants in numerous genes, but determining which are causal remains challenging. We hypothesized that the spatial distribution of missense variants in protein structures contains information about function and pathogenicity that can help prioritize variants of unknown significance (VUS) and elucidate the structural mechanisms leading to disease.

Results: To illustrate this approach in a clinical application, we analyzed 13 candidate missense variants in regulator of telomere elongation helicase 1 (RTEL1) identified in patients with Familial Interstitial Pneumonia (FIP).