title: BMI as a Modifiable Risk Factor for Type 2 Diabetes: Refining and Understanding Causal Estimates Using Mendelian Randomization.
abstract: This study focused on resolving the relationship between BMI and type 2 diabetes. The availability of multiple variants associated with BMI offers a new chance to resolve the true causal effect of BMI on type 2 diabetes; however, the properties of these associations and their validity as genetic instruments need to be considered alongside established and new methods for undertaking Mendelian randomization (MR). We explore the potential for pleiotropic genetic variants to generate bias, revise existing estimates, and illustrate value in new analysis methods. A two-sample MR approach with 96 genetic variants was used with three different analysis methods, two of which (MR-Egger and the weighted median) have been developed specifically to address problems of invalid instrumental variables. We estimate an odds ratio for type 2 diabetes per unit increase in BMI (kg/m(2)) of between 1.19 and 1.38, with the most stable estimate using all instruments and a weighted median approach (1.26 [95% CI 1.17, 1.34]). TCF7L2(rs7903146) was identified as a complex effect or pleiotropic instrument, and removal of this variant resulted in convergence of causal effect estimates from different causal analysis methods. This indicated the potential for pleiotropy to affect estimates and differences in performance of alternative analytical methods. In a real type 2 diabetes-focused example, this study demonstrates the potential impact of invalid instruments on causal effect estimates and the potential for new approaches to mitigate the bias caused.
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, U.K.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Corbin
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, U.K.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Richmond
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, U.K.
authors.forename: Kaitlin H
authors.initials: KH
authors.lastname: Wade
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, U.K. Department of Public Health and Primary Care, University of Cambridge, Cambridge, U.K.
authors.forename: Stephen
authors.initials: S
authors.lastname: Burgess
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, U.K. MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, U.K.
authors.forename: Jack
authors.initials: J
authors.lastname: Bowden
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, U.K.
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, U.K. n.j.timpson@bristol.ac.uk.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
mesh_terms: D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics; D058685:Genetic Pleiotropy / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D057182:Mendelian Randomization Analysis; D016017:Odds Ratio; D012307:Risk Factors; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics
chemical_list: C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein