Selecting instruments for Mendelian randomization in the wake of genome-wide association studies - PubMed (original) (raw)

. 2016 Oct;45(5):1600-1616.

doi: 10.1093/ije/dyw088. Epub 2016 Jun 24.

Karoline B Kuchenbaecker 3, Sonia Shah 4, Reecha Sofat 4 5, Michael V Holmes 4 6, Jon White 4, Jennifer S Mindell 7, Mika Kivimaki 7, Eric J Brunner 7, John C Whittaker 8 9, Juan P Casas 8, Aroon D Hingorani 4

Affiliations

Selecting instruments for Mendelian randomization in the wake of genome-wide association studies

Daniel I Swerdlow et al. Int J Epidemiol. 2016 Oct.

Abstract

Mendelian randomization (MR) studies typically assess the pathogenic relevance of environmental exposures or disease biomarkers, using genetic variants that instrument these exposures. The approach is gaining popularity-our systematic review reveals a greater than 10-fold increase in MR studies published between 2004 and 2015. When the MR paradigm was first proposed, few biomarker- or exposure-related genetic variants were known, most having been identified by candidate gene studies. However, genome-wide association studies (GWAS) are now providing a rich source of potential instruments for MR analysis. Many early reviews covering the concept, applications and analytical aspects of the MR technique preceded the surge in GWAS, and thus the question of how best to select instruments for MR studies from the now extensive pool of available variants has received insufficient attention. Here we focus on the most common category of MR studies-those concerning disease biomarkers. We consider how the selection of instruments for MR analysis from GWAS requires consideration of: the assumptions underlying the MR approach; the biology of the biomarker; the genome-wide distribution, frequency and effect size of biomarker-associated variants (the genetic architecture); and the specificity of the genetic associations. Based on this, we develop guidance that may help investigators to plan and readers interpret MR studies.

Keywords: Mendelian randomization; biomarkers; causal inference; genome-wide association study.

© The Author 2016. Published by Oxford University Press on behalf of the International Epidemiological Association.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

A: Mendelian randomization is a natural analogue of the classical randomized controlled trial (RCT). Random allocation of alleles at conception and the unidirectional flow of information from DNA sequence to endogenous biomarker phenotype allow causal inference of the type possible within the RCT framework. Genotype is generally unrelated to environmental exposures, thus reducing confounding. B: the Mendelian randomization model: the causal role of an exposure, P, on a disease state, D, is being evaluated. A genetic variant, G, is associated with biomarker P but not with confounders, U. Variant G is also associated with disease D and acts only through its effects on biomarker P. The model rests on three core assumptions: (i) the genetic instrument (G) is associated with the exposure or biomarker of interest (P); (ii) the genetic instrument (G) is independent of potential confounding factors (U) in the relationship between the exposure/biomarker (P) and the outcome (D); (iii) the outcome (D) is associated with the genetic instrument (G) only through the effect of the exposure/biomarker (P), and is in all other respects independent.

Figure 2.

Figure 2.

Mechanisms that may give rise to genetic pleiotropy and implications for MR analysis.

Figure 3.

Figure 3.

Illustrative guide to some of the key decisions in selecting instruments for MR analysis of disease biomarkers, based on the principles outlined in this review. The figure is intended to help plan a Mendelian randomization study of a disease-associated biomarker and should not be viewed as an inflexible decision tree. For additional considerations and details, please refer to the main text.

Comment in

References

    1. Davey Smith G, Ebrahim S. What can mendelian randomization tell us about modifiable behavioural and environmental exposures? BMJ 2005;330:107679. - PMC - PubMed
    1. Davey Smith G, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 2003;32:1–22. - PubMed
    1. Mendel G. Experiments in plant hybridisation Proceedings of Brunn Natural History Society, Brunn, 8 February and 8 March 1865. Brunn, Germany: Natural History Society of Brunn, 1866.
    1. Hingorani A, Humphries S. Nature’s randomized trials. Lancet 2005;366:1906–08. - PubMed
    1. Crick F. Central dogma of molecular biology. Nature 1970;227:561–63. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources