title: Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study: application to alcohol and cardiovascular traits.
abstract: BACKGROUND
  Mendelian randomization studies have so far restricted attention to linear associations relating the genetic instrument to the exposure, and the exposure to the outcome. In some cases, however, observational data suggest a non-linear association between exposure and outcome. For example, alcohol consumption is consistently reported as having a U-shaped association with cardiovascular events. In principle, Mendelian randomization could address concerns that the apparent protective effect of light-to-moderate drinking might reflect 'sick-quitters' and confounding.
  
  
  METHODS
  The Alcohol-ADH1B Consortium was established to study the causal effects of alcohol consumption on cardiovascular events and biomarkers, using the single nucleotide polymorphism rs1229984 in ADH1B as a genetic instrument. To assess non-linear causal effects in this study, we propose a novel method based on estimating local average treatment effects for discrete levels of the exposure range, then testing for a linear trend in those effects. Our method requires an assumption that the instrument has the same effect on exposure in all individuals. We conduct simulations examining the robustness of the method to violations of this assumption, and apply the method to the Alcohol-ADH1B Consortium data.
  
  
  RESULTS
  Our method gave a conservative test for non-linearity under realistic violations of the key assumption. We found evidence for a non-linear causal effect of alcohol intake on several cardiovascular traits.
  
  
  CONCLUSIONS
  We believe our method is useful for inferring departure from linearity when only a binary instrument is available. We estimated non-linear causal effects of alcohol intake which could not have been estimated through standard instrumental variable approaches.
authors.affiliation: Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Silverwood
authors.affiliation: Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Holmes
authors.affiliation: Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Dale
authors.affiliation: Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.affiliation: Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Whittaker
authors.affiliation: Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.affiliation: Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Leon
authors.affiliation: Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Palmer
authors.affiliation: Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.affiliation: Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Luisa
authors.initials: L
authors.lastname: Zuccolo
authors.affiliation: Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Casas
authors.affiliation: Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA and Institute of Cardiovascular Science, University College London, London, UK Faculty of Epidemiology and Population Health, Centre for Statistical Methodology and Bloomsbury Centre for Genetic Epidemiology and Statistics, London School of Hygiene and Tropical Medicine, London, UK, Department of Epidemiology and Public Health, University College London, London, UK, MRC Integrative Epidemiology Unit and School of Social and Community Medicine, University of Bristol, Bristol, UK, Genetics, R & D, GlaxoSmithKline, Stevenage, UK, Division of Health Sciences, University of Warwick, Warwick, Coventry, UK, Center for Applied Genomics
authors.forename: Frank
authors.initials: F
authors.lastname: Dudbridge
mesh_terms: D000426:Alcohol Dehydrogenase / Q000235:genetics; D000428:Alcohol Drinking / Q000453:epidemiology* / Q000235:genetics; D002318:Cardiovascular Diseases / Q000453:epidemiology*; D015984:Causality; D059647:Gene-Environment Interaction; D005838:Genotype; D006801:Humans; D057182:Mendelian Randomization Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: C489332:ADH1B protein, human; D000426:Alcohol Dehydrogenase
keywords: Mendelian randomization; alcohol consumption; cardiovascular disease; causal inference; instrumental variables; local average treatment effects