Limited associations of dopamine system genes with alcohol dependence and related traits in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD).

Owing to its involvement in a broad range of functions, alteration in dopamine (DA) activity appears to play a central role in the etiology and/or treatment of many psychiatric disorders. DA’s posited role in alcohol dependence (AD) stems from its involvement in the mesocorticolimbic reward pathway, which spans from the ventral tegmental area (VTA) to the nucleus accumbens (NA) and prefrontal cortex (Koob, 1992). DA was first implicated in mediating the effects of reward in Olds and Milner’s (1954) classic experiments. Subsequent behavioral studies have generated considerable additional evidence to show that dopaminergic transmission in the mesocorticolimbic pathway is essential to reinforcing reward (Schultz, 1998). Of all addictive substances, alcohol has created one of the greatest societal burdens (Rehm et al., 2009). AD is a clinically and etiologically heterogeneous condition that is 50 to 60% heritable (Dick et al., 2009; Prescott et al., 2006). Because of its etiological heterogeneity, considering subtypes of individuals with AD may increase power to detect underlying susceptibility variants. A recent latent class analysis of our sample found that cases could be divided into three classes based on comorbidities: a severe (S) class with the highest probabilities of all comorbidities and high novelty seeking (NS); a depressed (D) class with the highest probability of neuroticism and high probability of depression; and a mild (M) class with the lowest probabilities of all comorbidities (Sintov et al., 2010). These classes are consistent with the idea that alternate pathways to the development of AD exist, including negative affect regulation, in which alcohol consumption is a means of relieving negative mood states, and behavioral disinhibition, in which high consumption is part of an overall tendency to behave impulsively and to seek excitement (Sintov et al., 2010). The relatively independent nature of these pathways is supported by evidence that one common factor is largely responsible for the genetic susceptibility to internalizing disorders, while another common genetic factor explains most of the variation in externalizing disorders (Kendler et al., 2003). These common genetic liabilities may help explain why internalizing phenotypes, such as depression and anxiety/neuroticism, and disinhibitory phenotypes, including drug dependence (DD), antisocial behavior, and attention deficit/hyperactivity disorder (ADHD), are highly comorbid in many samples, including our Irish sample (Hasin et al., 2007; Kessler et al., 2006). As the mesocorticolimbic pathway may be involved in the rewarding aspects of externalizing behavior, DA genes are reasonable candidates for susceptibility to AD as well as other disinhibitory psychopathology. We considered AD, ADHD, antisocial personality disorder (ASPD), conduct disorder (CD), DD, and NS to be part of the externalizing spectrum. Several studies suggest that a disinhibitory personality style, including NS, shares a common genetic influence with disorders in the externalizing spectrum (Jang et al., 2000; Krueger et al., 2002; Young et al., 2000). No twin studies have reported a direct genetic overlap between ADHD and AD; however, we included this phenotype in the disinhibitory spectrum because childhood/early adolescent studies suggest ADHD shares genetic liability with CD (Dick et al., 2005; Eaves et al., 2000; Knopik et al., 2009; Nadder et al., 2002; Silberg et al., 1996; Tuvblad et al., 2009). We examined ten DA system genes, including the following: the five receptors, DRD1-D5; two transporters, solute carrier family 18 member A2 (SLC18A2 or vesicular monoamine transporter type 2, VMAT2) and solute carrier family 6, member 3 (SLC6A3 or dopamine active transporter, DAT or DAT1); and three enzymes, tyrosine hydroxylase (TH), dopa decarboxylase (DDC), and catechol-O-methyltransferase (COMT). These genes are related to DA binding, biosynthesis, and catabolism, and they cover about 60% of the genes with these Gene Ontology terms. If no studies of association between a particular gene and trait are discussed below, we are unaware of any reports (either positive or negative) with rigorous methodology that have examined these associations.