Genome-wide association study of a quantitative disordered gambling trait

Quantitative GeneticsGenetic EpidemiologyMolecular EpidemiologyQueensland Institute of Medical Research, Brisbane, QLD, Australia, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USADepartment of Psychological Sciences, University of Missouri, Columbia, MO, USA.
Addiction Biology (Impact Factor: 5.36). 07/2012; 18(3). DOI: 10.1111/j.1369-1600.2012.00463.x
Source: PubMed


Disordered gambling is a moderately heritable trait, but the underlying genetic basis is largely unknown. We performed a genome-wide association study (GWAS) for disordered gambling using a quantitative factor score in 1312 twins from 894 Australian families. Association was conducted for 2 381 914 single-nucleotide polymorphisms (SNPs) using the family-based association test in Merlin followed by gene and pathway enrichment analyses. Although no SNP reached genome-wide significance, six achieved P-values < 1 × 10(-5) with variants in three genes (MT1X, ATXN1 and VLDLR) implicated in disordered gambling. Secondary case-control analyses found two SNPs on chromosome 9 (rs1106076 and rs12305135 near VLDLR) and rs10812227 near FZD10 on chromosome 12 to be significantly associated with lifetime Diagnostic and Statistical Manual of Mental Disorders, fourth edition pathological gambling and South Oaks Gambling Screen classified probable pathological gambling status. Furthermore, several addiction-related pathways were enriched for SNPs associated with disordered gambling. Finally, gene-based analysis of 24 candidate genes for dopamine agonist-induced gambling in individuals with Parkinson's disease suggested an enrichment of SNPs associated with disordered gambling. We report the first GWAS of disordered gambling. While further replication is required, the identification of susceptibility loci and biological pathways will be important in characterizing the biological mechanisms that underpin disordered gambling.

  • Source
    • "Clinically, a study of 139 healthy controls found that COMT met/met homozygotes were more likely to be at-risk gamblers and mild problem drinkers compared to Val/Val homozygotes (Guillot et al., 2014). To further complicate the picture, a small genome-wide association study from the national communitybased Australian Twin Registry did not find a significant association between COMT rs4680 and disordered gambling in 1312 twins (Lind et al., 2013). One potential explanation for discordant results in relation to cognition and the COMT polymorphism is that different optimal levels of dopamine are required for different cognitive functions; there may be a 'trade off' with higher dopamine (as seen with the Met variant) being associated with relatively superior improvement in some domains, with relative impairments in others. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuropsychological studies of adults with problem gambling indicate impairments across multiple cognitive domains. Catechol-O-methyltransferase (COMT) plays a unique role in the regulation of dopamine in the prefrontal cortex, and has been implicated in the cognitive dysfunction evident in problem gambling. This study examined adults with varying levels of gambling behavior to determine whether COMT genotype was associated with differences in gambling symptoms and cognitive functioning. 260 non-treatment-seeking adults aged 18-29 years with varying degrees of gambling behavior provided saliva samples for genotyping COMT val158met (rs4680). All subjects underwent clinical evaluations and neurocognitive assessment of decision-making, working memory, and impulsivity. The Val/Val COMT genotype was associated with the largest percentage of subjects with gambling disorder (31.8%), a rate significantly different from the Val/Met (13.2%) group (p = 0.001). The Val/Val COMT group was also associated with significantly more gambling disorder diagnostic criteria being met, greater frequency of gambling behavior, and significantly worse cognitive performance on the Cambridge Gamble Task (risk adjustment and delay aversion) and the Spatial Working Memory task (total errors). This study adds to the growing literature on the role of COMT in impulsive behaviors by showing that the Val/Val genotype was associated with specific clinical and cognitive elements among young adults who gamble, in the absence of differences on demographic measures and other cognitive domains. Future work should consider using genotyping to explore whether certain polymorphisms predict subsequent development of impulsive behaviors including gambling disorder, and treatment outcomes. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · May 2015 · Journal of Psychiatric Research
  • Source
    • "COMT Met homozygotes reported greater levels of gambling problems than Val homozygotes and were about twice as likely to be at-least-at-risk gamblers in comparison to Val carriers (small-to-medium effect sizes; Cohen 1988/2009). In contrast with current results, a recent genome-wide association study did not find an association between COMT rs4680 and disordered gambling (Lind et al., 2013); however, that study examined a quantitative factor score derived from four measures of gambling involvement and two measures of gambling problems (one of which was the SOGS), whereas the current study focused on gambling problems as measured by the SOGS, which may account for this discrepancy. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Disordered gambling and alcohol dependence are influenced by unique and shared genetic factors. Although the evidence is mixed, some research has linked catechol-O-methyltransferase (COMT) rs4680 (or COMT Val158Met) to the development of gambling or drinking problems; however, no molecular genetic study has jointly examined gambling and drinking problems. Furthermore, the majority of past studies examined gambling or drinking problems using a case–control design. The purpose of the current study was to examine associations of COMT rs4680 with dimensionally and categorically measured gambling and drinking problems in a nonclinical sample (139 Caucasian adults). The current study found that COMT rs4680 was related to both dimensionally and categorically measured gambling and drinking problems. It appears that the COMT Met/Met genotype may be a genetic risk factor that contributes to the development of both gambling and drinking problems.
    Full-text · Article · Jun 2014 · Journal of Gambling Studies
  • Source
    • "l-DOPA is then decarboxylated by aromatic l-amino acid decarboxylase [AADC; also known as dopa decarboxylase (DDC)] to DA (Elsworth and Roth, 2009). Variants [single nucleotide polymorphisms (SNPs)] in the DDC gene have been associated with nicotine (Ma et al., 2005; Yu et al., 2006; Zhang et al., 2006), alcohol (Agrawal et al., 2011; Kristjansson et al., 2012) and illicit drug (Hack et al., 2011) misuse, and most recently, disordered gambling (Lind et al., 2012). Importantly, Derringer et al. (2010) found that a combination of multiple SNPs in the DDC gene predicted individual variation in sensation seeking traits, suggesting that genetic variation in DA synthesis is related to broad EXT risk. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Impulse control disorders (ICDs), including disordered gambling, can occur in a significant number of patients with Parkinson's disease (PD) receiving dopaminergic therapy. The neurobiology underlying susceptibility to such problems is unclear, but risk likely results from an interaction between dopaminergic medication and a pre-existing trait vulnerability. Impulse control and addictive disorders form part of a broader psychopathological spectrum of disorders, which share a common underlying genetic vulnerability, referred to as externalizing. The broad externalizing risk factor is a continuously varying trait reflecting vulnerability to various impulse control problems, manifested at the overt level by disinhibitory symptoms and at the personality level by antecedent traits such as impulsivity and novelty/sensation seeking. Trait "disinhibition" is thus a core endophenotype of ICDs, and a key target for neurobiological investigation. The ventral striatal dopamine system has been hypothesized to underlie individual variation in behavioral disinhibition. Here, we examined whether individual differences in ventral striatal dopamine synthesis capacity predicted individual variation in disinhibitory temperament traits in individuals with PD. Eighteen early-stage male PD patients underwent 6-[F]Fluoro-l-DOPA (FDOPA) positron emission tomography scanning to measure striatal dopamine synthesis capacity, and completed a measure of disinhibited personality. Consistent with our predictions, we found that levels of ventral, but not dorsal, striatal dopamine synthesis capacity predicted disinhibited personality, particularly a propensity for financial extravagance. Our results are consistent with recent preclinical models of vulnerability to behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of potential vulnerability to impulse control problems in PD and other disorders.
    Full-text · Article · Feb 2013 · Frontiers in Psychology
Show more