Candidate Gene Studies in Problem Gambling Dr. James L. Kennedy, MD, FRCP(C) Neuroscience Research Department Centre for Addiction and Mental Health Dr. Nigel Turner, PhD Centre for Addiction and Mental Health Dr. Daniela S. S. Lobo, MD, PhD Neuroscience Research Department Centre for Addiction and Mental Health (Collaborator in this study) April 1, 2007 Final report prepared for the Ontario Problem Gambling Research Centre (OPGRC) Disclaimer: Opinions expressed in this final report are those of the investigator(s), and do not necessarily represent the views of the OPGRC. 2 Table of Contents Acknowledgements …………………………………………………………… 3 Abstract …………………………………………………………… 4 Introduction …………………………………………………………… 5 Research Hypotheses …………………………………………………………… 13 Method …………………………………………………………… 13 Results …………………………………………………………… 15 Discussion …………………………………………………………… 26 Study Limitations …………………………………………………………… 28 References …………………………………………………………… 31 3 Acknowledgements This report was funded by a grant from the Ontario Problem Gambling Research Centre (OPGRC). The ideas expressed are those of the authors and do not necessarily reflect those of either the OPGRC or the Centre for Addiction and Mental Health. 4 Abstract A growing body of evidence is demonstrating the susceptibility to become a pathological gambler has a relatively large genetic component. When exposed to the same environmental gambling opportunities, only some individuals develop symptoms of problem or pathological gambling (PG), which supports the presence of a biological susceptibility to develop the disorder in addition to environmental factors. Studies investigating the influence of genetic factors on the development of PG have provided strong evidence towards the heritability of PG vulnerability. Based on the current literature the monoaminergic systems and, in particular, the dopaminergic pathway, continue to represent the principal biological component involved in the etiology of PG. Previous molecular genetic studies in PG have been conducted to test dopamine and serotonin system genes as candidates, and concluded that variation in these genes may determine an increased risk of suffering from PG, but interpretation of these results remain limited by the sample sizes used and by the technology available at the time these studies were performed. The current study is the third part of our continuing effort to understand the genetic causes of PG. The first part, Special Problems in gambling: Attention Deficit Hyperactivity Disorder (ADHD) and pathways to problem gambling, focused on assessing the relative importance of emotional, experiential/behavioral, and physiological (genetic) aspects of the disorder. The study recruited and characterized PGs, as well as a control sample of non-problem, but active, social gamblers. The second part, Identification of genetic risk factors for pathological gambling (Kennedy, Muglia, Jain, & Turner, 2004), collected data from a control sample of infrequent or non-gamblers to act as a comparison to problem and non-problem social gamblers. Analysis of these samples showed indicators of association with genetic variants in the serotonin transporter, dopamine D1 and D4 receptors, and monoamine oxidase A. A larger sample was required to dissect and understand these findings. The aim of the current project was to collect a larger sample of an additional 300 PGs and controls to perform statistically powerful genetic tests to confirm and extend our preliminary findings. We found two variants of the D4 receptor gene to be associated with PG and that emotional vulnerability and impulsivity account for a large portion of the variance in PG. In the future, we will use the data from this study in combination with our dataset of ADHD patients to gain insight into the overlap of genetic risk factors in PG and ADHD, and also comorbid disorders in PG, such as depression and substance abuse. Key words: pathological gambling, problem gambling, candidate gene studies, dopamine. 5 Introduction Background Gambling is the act of betting something of value (usually money) on an uncertain outcome in the hope of a winning. The Diagnostic and Statistical Manual of Mental Disorders (A.P.A., 2000) defines pathological gambling (PG) as a persistent and recurrent maladaptive gambling behaviour that consequently disrupts personal, family, or vocational pursuits. An estimated 86% of the adult US population has gambled at least once in their lives (N.O.R.C, 1999). Most people who gamble do not develop a gambling problem; however, a fraction of these individuals will gradually escalate to larger bets and greater risks. A meta- analysis of 119 PG prevalence studies conducted in the United States and Canada reported the lifetime prevalence of PG in adults at 1.6%, with an additional 3.9% having a sub-clinical level of gambling problems, or problem gambling (PrG) (Shaffer, Hall, & Vander Bilt, 1999). A growing body of evidence is demonstrating that there is a significant genetic susceptibility to PG. When exposed to the same environmental gambling opportunities, only some individuals will develop symptoms of PG, supporting the presence of a biological susceptibility in developing the disorder in combination with environmental components (Murray, 1993). Family studies are one of the most common strategies to investigate the inheritance of complex traits or disorders, through the assessment of blood relatives of an affected individual (proband). The information is obtained either by asking the proband about their family members (family-history method) or through direct interview of the relatives (family-study method). This study design provides information on the familial segregation of the disorder, which can be the result of not only genetic, but also environmental factors. In order to determine whether a non-Mendelian disorder or trait runs in families, it is necessary to quantify the risk of a proband’s relatives to be affected by the disease compared with the population risk of the disease. This measure can be calculated for all relatives and values will be closer to one in distant relatives (Risch, 1990). Another approach to family studies is to compare the frequency of the disorder or trait under investigation and comorbid disorders in relatives of the proband and compare the obtained data to relatives of control subjects. These studies are usually conducted on first-degree relatives of the proband and comprise the majority of family studies conducted on pathological gambling. Twin studies can help elucidate the extent to which genetic factors are responsible for the development of a certain trait or disorder (phenotype). Monozygotic (MZ) or identical twins share 100% of their genes because they are derived from the same zygote. Dizygotic (DZ) or fraternal twins share, on average, 50% of their genes as do any siblings. Thus, when genetic factors account for most of the variance of a phenotype, MZ twins will present a significantly higher concordance rate compared to DZ twins. This study design assumes that twins raised in the same setting are exposed for the most part to the same environment (shared family environment). Both MZ and DZ twins are raised during the same time period, thus sharing experiences that are related to a specific time frame in the family’s history, which might not be possible for non-twins. However, environmental exposure can be different even in twins raised together, for example for experiences with different friends and the type of relationship each twin develops with the parents. This type of environmental exposure is usually referred to as 6 nonshared or unique environmental experiences. Published twin and family studies on PG are reviewed below. Family Studies in Pathological Gambling Initial evidence towards family aggregation of pathological gambling came from the finding that the risk of pathological gambling was associated with parental gambling (Jacobs, 1989; H. R. Lesieur & Blume, 1990; H. R. Lesieur et al., 1991; H. R. Lesieur & Heineman, 1988), and that children of pathological gamblers were more vulnerable to develop dysfunctional behaviors (Jacobs, 1989; H. R. R. Lesieur, J., 1989). Gambino and colleagues (Gambino, 1993) investigated the frequency of perceived addictive problems for parents and grandparents in a sample of 93 United States Veterans Affairs population of drug and alcohol abusers. Gambling behavior was assessed through the South Oaks Gambling Screen in which scores of 3 or 4 indicate a potential pathological gambler or a problem gambler and scores >5 indicate a potential pathological gambler (H. R. Lesieur & Blume, 1987). Through the South Oaks Gambling Screen scores 17.3% (n=16) of the subjects were considered as probable pathological gamblers and 14% (n=13) as potential pathological gamblers. Subjects who reported gambling problems among their parents had a three times higher liability of scoring as a probable pathological gambler. Interestingly, those who perceived their grandparents as problem gamblers were at 12 times the risk of being a problem gambler compared to those who did not report gambling problems among their grandparents. Some studies have investigated the exposure to gambling in families. Gupta and Derevensky (Gupta & Derevensky, 1997) assessed a sample of 477 children 9–14 years of age who reported gambling on a regular basis, of whom 86% reported gambling with their relatives. Although there is no evaluation regarding problem or pathological gambling among these youths, this finding points