title: Mendelian randomization in health research: using appropriate genetic variants and avoiding biased estimates.
abstract: Mendelian randomization methods, which use genetic variants as instrumental variables for exposures of interest to overcome problems of confounding and reverse causality, are becoming widespread for assessing causal relationships in epidemiological studies. The main purpose of this paper is to demonstrate how results can be biased if researchers select genetic variants on the basis of their association with the exposure in their own dataset, as often happens in candidate gene analyses. This can lead to estimates that indicate apparent "causal" relationships, despite there being no true effect of the exposure. In addition, we discuss the potential bias in estimates of magnitudes of effect from Mendelian randomization analyses when the measured exposure is a poor proxy for the true underlying exposure. We illustrate these points with specific reference to tobacco research.
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, 12a Priory Road, Bristol BS8 1TU, UK. Electronic address: amy.taylor@bristol.ac.uk.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Taylor
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Davies
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, 12a Priory Road, Bristol BS8 1TU, UK; MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Ware
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: VanderWeele
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, 12a Priory Road, Bristol BS8 1TU, UK.
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Munafò
mesh_terms: D015982:Bias; D015984:Causality; D015986:Confounding Factors, Epidemiologic; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D057182:Mendelian Randomization Analysis / Q000379:methods*; D012107:Research Design; D012907:Smoking / Q000235:genetics
keywords: Causal inference; Instrumental variable; Mendelian randomization; Smoking; Tobacco