Health Services and Outcomes Research Methodology

, Volume 11, Issue 1, pp 54-78

First online:

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

  • George L. WehbyAffiliated withDepartment of Health Management and Policy, College of Public Health, University of Iowa Email author 
  • , Astanand JugessurAffiliated withNorwegian Institute of Public Health
  • , Jeffrey C. MurrayAffiliated withUniversity of Iowa
  • , Lina M. MorenoAffiliated withUniversity of Iowa
  • , Allen WilcoxAffiliated withNational Institute of Environmental Health Sciences
  • , Rolv T. LieAffiliated withUniversity of Bergen

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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