Orienting the causal relationship between imprecisely measured traits using GWAS summary data

Inference about the causal structure that induces correlations between two traits can be achieved by combining genetic associations with a mediation-based approach, as is done in the causal inference test (CIT). However, we show that measurement error in the phenotypes can lead to the CIT inferring...

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Vydáno v:	PLoS genetics Ročník 13; číslo 11; s. e1007081
Hlavní autoři:	Hemani, Gibran, Tilling, Kate, Davey Smith, George
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 17.11.2017 Public Library of Science (PLoS)
Témata:	Analysis Bias Biology and life sciences Computer and Information Sciences DNA Methylation Gene expression Gene Expression Regulation Genetic Association Studies - methods Genetic research Genome-Wide Association Study - methods Genomics Measurement Mendelian Randomization Analysis - methods Methods Methylation Phenotype Physical Sciences Research and Analysis Methods Sample Size Social Sciences
ISSN:	1553-7404, 1553-7390, 1553-7404
On-line přístup:	Získat plný text
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Popis
Shrnutí:	Inference about the causal structure that induces correlations between two traits can be achieved by combining genetic associations with a mediation-based approach, as is done in the causal inference test (CIT). However, we show that measurement error in the phenotypes can lead to the CIT inferring the wrong causal direction, and that increasing sample sizes has the adverse effect of increasing confidence in the wrong answer. This problem is likely to be general to other mediation-based approaches. Here we introduce an extension to Mendelian randomisation, a method that uses genetic associations in an instrumentation framework, that enables inference of the causal direction between traits, with some advantages. First, it can be performed using only summary level data from genome-wide association studies; second, it is less susceptible to bias in the presence of measurement error or unmeasured confounding. We apply the method to infer the causal direction between DNA methylation and gene expression levels. Our results demonstrate that, in general, DNA methylation is more likely to be the causal factor, but this result is highly susceptible to bias induced by systematic differences in measurement error between the platforms, and by horizontal pleiotropy. We emphasise that, where possible, implementing MR and appropriate sensitivity analyses alongside other approaches such as CIT is important to triangulate reliable conclusions about causality.
Bibliografie:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors have declared that no competing interests exist.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1007081