An atlas of polygenic risk score associations to highlight putative causal relationships across the human phenome

• Published in: eLife Vol. 8
• Main Authors: Richardson, Tom G, Harrison, Sean, Hemani, Gibran, Davey Smith, George
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 05.03.2019; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Cardiovascular disease; causal inference; Cognitive ability; Databases, Genetic; Development and progression; Disease susceptibility; Diseases; Genes; Genetic aspects; genetic liability; Genetic Predisposition to Disease; Genetic research; Genetics and Genomics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Heart diseases; Humans; Hypertension; Internet software; Legal liability; Liability; Mediation; Medical research; Mendelian randomization; Mental disorders; Multifactorial Inheritance; Novels; Obesity; phenome-wide association study; Polygenic inheritance; polygenic risk scores; Risk Assessment; Risk factors; Schizophrenia; Schizophrenia - genetics; Smoking cessation; Tools and Resources; Triglycerides; United Kingdom; United Kingdom; United Kingdom > UK; genetic liability; genetics; genomics; Mendelian randomization; phenome-wide association study; causal inference; human; polygenic risk scores
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.43657

The age of large-scale genome-wide association studies (GWAS) has provided us with an unprecedented opportunity to evaluate the genetic liability of complex disease using polygenic risk scores (PRS). In this study, we have analysed 162 PRS (p<5×10 ) derived from GWAS and 551 heritable traits from the UK Biobank study (N = 334,398). Findings can be investigated using a web application (http:‌//‌mrcieu.‌mrsoftware.org/‌PRS‌_atlas/), which we envisage will help uncover both known and novel mechanisms which contribute towards disease susceptibility. To demonstrate this, we have investigated the results from a phenome-wide evaluation of schizophrenia genetic liability. Amongst findings were inverse associations with measures of cognitive function which extensive follow-up analyses using Mendelian randomization (MR) provided evidence of a causal relationship. We have also investigated the effect of multiple risk factors on disease using mediation and multivariable MR frameworks. Our atlas provides a resource for future endeavours seeking to unravel the causal determinants of complex disease.