Genes as instruments for studying risk behavior effects: an application to maternal smoking and orofacial clefts

  • George L. Wehby
  • Astanand Jugessur
  • Jeffrey C. Murray
  • Lina M. Moreno
  • Allen Wilcox
  • Rolv T. Lie


This study uses instrumental variable (IV) models with genetic instruments to assess the effects of maternal smoking on the child’s risk of orofacial clefts (OFC), a common birth defect. The study uses genotypic variants in neurotransmitter and detoxification genes relateded to smoking as instruments for cigarette smoking before and during pregnancy. Conditional maximum likelihood and two-stage IV probit models are used to estimate the IV model. The data are from a population-level sample of affected and unaffected children in Norway. The selected genetic instruments generally fit the IV assumptions but may be considered “weak” in predicting cigarette smoking. We find that smoking before and during pregnancy increases OFC risk substantially under the IV model (by about 4–5 times at the sample average smoking rate). This effect is greater than that found with classical analytic models. This may be because the usual models are not able to consider self-selection into smoking based on unobserved confounders, or it may to some degree reflect limitations of the instruments. Inference based on weak-instrument robust confidence bounds is consistent with standard inference. Genetic instruments may provide a valuable approach to estimate the “causal” effects of risk behaviors with genetic-predisposing factors (such as smoking) on health and socioeconomic outcomes.


Smoking Genetic instrumental variables Mendelian randomization Oral clefts Birth defects Child health 

Supplementary material

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Supplementary material 1 (DOCX 36 kb)


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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • George L. Wehby
    • 1
  • Astanand Jugessur
    • 2
  • Jeffrey C. Murray
    • 3
  • Lina M. Moreno
    • 3
  • Allen Wilcox
    • 4
  • Rolv T. Lie
    • 5
  1. 1.Department of Health Management and PolicyCollege of Public Health, University of IowaIowa CityUSA
  2. 2.Norwegian Institute of Public HealthOsloNorway
  3. 3.University of IowaIowaUSA
  4. 4.National Institute of Environmental Health SciencesDurhamUSA
  5. 5.University of BergenBergenNorway

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