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

BioRxiv : the Preprint Server for Biology
Tom G. RichardsonGeorge Davey Smith

Abstract

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<5x10-05) 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.

Related Concepts

Cognition
Disease Susceptibility
Schizophrenia
Fracture of First Cervical Vertebra
Genome-Wide Association Study
Study
Mendelian Randomization Analysis
Clinical Study Follow-up

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