Evidence within the literature and other studies has suggested a role in the influence of genetics on adolescent tobacco smoke, and eventual addiction to that substance (Li 2003). Genome wide association studies (GWAS) have provided a very robust methodology for identification of causal genetic influences on complex disease phenotypes.

The abuse of tobacco in adolescence can cause addiction in future life increasing your chance to have a lower mortality age (Aklin et al. 2009). It is a very important societal problem as tobacco smoke has one of the highest death rates of a preventable death rates, tobacco use kills approximately 5-6 million people annually worldwide, accounting for 1 in 5 of all male deaths and 1 in 20 of all female deaths. It is predicted to kill 450 million adults, on the basis of current consumption, between 2000 and 2050 (Jha 2009). The Caporaso et al. (2009) genome wide association study into different smoking phenotypes, such as duration and age of smoking initiation, found no loci at genome-wide significance (pless than 10-7), although there were some suggestive hits. Therefore refinement of the phenotype to use a more biological measure may contribute more to our understanding of this disorder and increase of number of individuals as we would be able to use more of the ALSPAC sample.

Tobacco abuse contains the psychotropic chemical nicotine; cotinine is an alkaloid found in tobacco and is a metabolite of nicotine. This substance is a good proxy for amount of nicotine within the individual and therefore the amount smoked by the individual. This phenotype will not be prone to reporter bias; although the chemical is short-lived within the body therefore there could be some measurement error according to the smoking behaviour of the individual. The amount of this substance will be the principle phenotype used within this GWAS to investigate whether any possible signals of genetic loci at genome-wide significance (pless than 10-7) can be found. This can then be compared to other candidate gene studies to investigate if any of the genetic loci of biological relevance can be found within the signals, or if novel signals have been discovered for the amount of cotinine within an individual. The best measure of this would be at 15 + years of age, as this is around a similar time to when we have self reported measure of tobacco use, which can be compared as a control measure. Cotinine can be measured in the urine or saliva samples which ALSPAC receive from clinics.

The principle aim of this project is to discover novel genetic loci which may contribute toward the complex disorder of tobacco abuse, which may give us some early indications towards adolescent abuse to adult addiction. This project has a novel approach by using the quantitative biological sampling of cotinine, which has no reporter bias and is generally less biased than using questionnaire data which is common for previous studies.

For this project cotinine levels would be needed on all individuals where it has been measured, also the genetic information for ALSPAC which is currently available. Also covariates could be retrieved from the ALSPAC folder from previous questionnaires. We will undergo the GWAS for the continuous variable of cotinine using related programmes; the covariates would be measured for an association with the main phenotype and then added to the GWAS. Covariates could include parental smoking behaviours, parental smoking, socio-economic status and phenotypes related to smoking.

References

Aklin, W.M., Moolchan, E.T., Luckenbaugh, D.A., & Ernst, M. 2009. Early tobacco smoking in adolescents with externalizing disorders: Inferences for reward function. Nicotine Tobacco Research, 11, (6) 750-755 available from: http://ntr.oxfordjournals.org/cgi/content/abstract/11/6/750

Jha, P. 2009. Avoidable global cancer deaths and total deaths from smoking. Nat Rev Cancer, 9, (9) 655-664 available from: http://dx.doi.org/10.1038/nrc2703

Li, M.D. 2003. The Genetics of Smoking Related Behavior: A Brief Review. The American Journal of the Medical Sciences, 326, (4) available from: http://journals.lww.com/amjmedsci/Fulltext/2003/10000/The_Genetics_of_Smoking_Related_Behavior__A_Brief.3.aspx