Maternal smoking has been linked to a number of poor outcomes in offspring, including conduct disorder and attention-deficit hyperactivity disorder (1). This finding has been remarkably consistent and replicated across multiple studies (2, 3). However, it is uncertain whether this association is causal, or if it is due to maternal risk factors that predispose the mother and offspring to substance abuse in addition to these disorders (2). Several studies have found that a latent variable predisposing both mother and child to externalizing is a better model for the increase in risk (4, 5), while others have found that smoking during pregnancy has a direct, independent association with both ADHD and antisocial behavior (6-8). Overall, the results imply that maternal smoking may have a direct, causal effect on ADHD, but antisocial behavior, ADHD, and substance abuse share common risk factors that may account for some of this relationship.

Conduct disorder, ADHD, and substance abuse disorders all fall into the spectrum of externalizing, an empirically derived personality factor that accounts for their genetic and phenotypic overlap (9, 10). Previous studies have implied that the molecular basis for these disorders lies in dysfunction of the dopamine system (11), finding signification associations with dopaminergic genes (12, 13). Studies have also found interaction effects between maternal smoking and dopamine genes (14, 15). Again, the link could be causal, or due to indirect overlap of genetic risk.

We intend on performing Bidirectional reciprocal Mendelian Randomization analysis using genome-wide scores to disentangle the relationship between maternal smoking and conduct disorder/ADHD. We will use genome-wide meta-analyses of smoking, conduct disorder and ADHD supplied by other groups in order to construct genome-wide scores in ALSPAC mothers (smoking) and ALSPAC children (conduct disorder, ADHD). We will then perform bidirectional reciprocal Mendelian Randomization to attempt to inform on causality between these variables.

1. Weissman, M. M., Warner, V., Wickramaratne, P. J., & Kandel, D. B. (2002). Maternal smoking during pregnancy and psychopathology in offspring followed to adulthood. Journal of American Academy of Child and Adolescent Psychiatry, 38(7), 892-899.

2. Wakschlag, L. S., Pickett, K. E., Cook, E., Benowitz, N. L., Leventhal, B. L. (2002). Maternal Smoking During Pregnancy and Severe Antisocial Behavior in Offspring: A Review. American Journal of Public Health, 92(6), 966-974.

3. Langley, K., Rice, F., van den Bree, M. B., & Thapar, A. (2005). Maternal smoking during pregnancy as an environmental risk factor for attention deficit hyperactivity disorder behaviour. A review. Minerva Pediatrica,57(6), 359-371.

4. Silberg, J. L., Parr, T., Neale, M. C., Rutter, M., Angold, A., & Eaves, L. J. (2003). Maternal Smoking During Pregnancy and Risk to Boys' Conduct Disturbance: An Examination of the Causal Hypothesis. Biological Psychiatry, 53,130-135.

5. D'Onofrio, B. M., van Hulle, C. A., Waldman, I. W., Rodgers, J. L., Harden, K. P., Rathouz, P. J., & Lahey, B. B. (2008). Smoking during pregnancy and offspring externalizing problems: An exploration of genetic and environmental confounds. Development and Psychopathology, 20, 139-164.

6. Button, T. M. M., Thapar, A., McGuffin, P. (2005). Relationship between antisocial behaviour, attention-deficit hyperactivity disorder and maternal prenatal smoking. The British Journal of Psychiatry, 187, 155-160.

7. Nigg, J. T., Breslau, N. (2007). Prenatal Smoking Exposure, Low Birth Weight, and Disruptive Disorders. Journal of the American Academy of Child and Adolescent Psychiatry, 46(3), 362-369.

8. Thapar, A., Fowler, T., Rice, F., Scourfield, J., van den Bree, M. B., Thomas, H., Harold, G., Hay, D. (2003). Maternal Smoking During Pregnancy and Attention Deficit Hyperactivity Disorder Symptoms in Offspring. American Journal of Psychiatry, 160(11), 1985-1989.

9. Krueger, R. F., Markon, K. E., Patrick, C. J., Benning, S. D., & Kramer, M. D. (2007). Linking Antisocial Behavior, Substance Use, and Personality: An Integrative Quantitative Model of the Adult Externalizing Spectrum. Journal of Abnormal Psychology, 116(4), 645-666.

10. Krueger, R. F., Hicks, B. M., Patrick, C. J., Carlson, S. R., Iacono, W. J., McGue, M. (2002). Etiologic Connections Among Substance Dependence, Antisocial Behavior, and Personality: Modeling the Externalizing Spectrum. Journal of Abnormal Psychology, 111(3), 411-424.

11. Solanto, M. V. (2002). Dopamine dysfunction in AD/HD: integrating clinical and basic neuroscience research. Behavioural Brain Research, 130(1-2), 65-71.

12. Li, D., Sham, P. C., Owen, M. J., & He, L. (2006). Meta-analysis shows significant association between dopamine system genes and attention-deficit hyperactivity disorder (ADHD). Human Molecular Genetics, 15(14), 2276-2284.

13. Comings, D. E., Gade-Andavolu, R., Gonzalez, N., Wu, S., Muhleman, D., Blake, H., Dietz, G., Saucier, G., & MacMurray, J. P. (2000). Comparison of the role of dopamine, serotonin, and noradrenaline genes in ADHD, ODD and conduct disorder: multivariate regression analysis of 20 genes. Clinical Genetics, 57(3), 178-196.

14. Neuman, R. J., Lobos, E., Reich, W., Henderson, C. A., Sun, L., Todd, R. D. (2007). Prenatal smoking exposure and dopaminergic genotypes interact to cause a severe ADHD subtype. Biological Psychiatry, 61(12), 1320-1328.

15. Kahn, R. S., Khoury, J., Nichols, W. C., Lamphear, B. P. (2003). Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional behaviors. The Journal of Pediatrics, 143(1), 104-110.