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Davey Smith, G.

Publications and source records attributed to Davey Smith, G..

111 records · Page 7Linked to original sources

Mendelian randomization: a novel approach for the prediction of adverse drug events and drugrepurposing opportunities

Identification of unintended drug effects, specifically drug repurposing opportunities and adverse drug events, maximizes the benefit of a drug and protects the health of patients. However, current observational research methods are subject to several biases. These include confounding by indication, reverse causality, and missing data. We propose that Mendelian randomization (MR) offers a novel approach for the prediction of unintended drug effects. In particular, we advocate the synthesis of evidence from this method and other approaches, in the spirit of triangulation, to improve causal inferences concerning drug effects. MR overcomes some of the limitations associated with the existing methods in this field. Furthermore, it can be applied either pre- or post-approval of the drug and could therefore prevent the potentially harmful exposure of patients in clinical trials and beyond. The potential of MR as a pharmacovigilance and drug repurposing tool is yet to be realized and could both help prevent adverse drug events and identify novel indications for existing drugs in the future.

pharmacology and toxicology↗

MR-Base: a platform for systematic causal inference across the phenome using billions of genetic associations

Published genetic associations can be used to infer causal relationships between phenotypes, bypassing the need for individual-level genotype or phenotype data. We have curated complete summary data from 1094 genome-wide association studies (GWAS) on diseases and other complex traits into a centralised database, and developed an analytical platform that uses these data to perform Mendelian randomization (MR) tests and sensitivity analyses (MR-Base, http://www.mrbase.org). Combined with curated data of published GWAS hits for phenomic measures, the MR-Base platform enables millions of potential causal relationships to be evaluated. We use the platform to predict the impact of lipid lowering on human health. While our analysis provides evidence that reducing LDL-cholesterol, lipoprotein(a) or triglyceride levels reduce coronary disease risk, it also suggests causal effects on a number of other non-vascular outcomes, indicating potential for adverse-effects or drug repositioning of lipid-lowering therapies.

epidemiology↗

Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

Autism spectrum disorder (ASD) risk is influenced by both common polygenic and de novo variation. The purpose of this analysis was to clarify the influence of common polygenic risk for ASDs and to identify subgroups of cases, including those with strong acting de novo variants, in which different types of polygenic risk are relevant. To do so, we extend the transmission disequilibrium approach to encompass polygenic risk scores, and introduce the polygenic transmission disequilibrium test. Using data from more than 6,400 children with ASDs and 15,000 of their family members, we show that polygenic risk for ASDs, schizophrenia, and greater educational attainment is over transmitted to children with ASDs in two independent samples, but not to their unaffected siblings. These findings hold independent of proband IQ. We find that common polygenic variation contributes additively to risk in ASD cases that carry a very strong acting de novo variant. Lastly, we find evide ...

genetics↗