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: 5.93). 07/2012; 18(3). DOI: 10.1111/j.1369-1600.2012.00463.x
Source: PubMed

ABSTRACT 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.

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    • "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. "
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    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.
    Journal of Psychiatric Research 05/2015; DOI:10.1016/j.jpsychires.2015.04.029
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    • "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. "
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    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.
    Journal of Gambling Studies 06/2014; DOI:10.1007/s10899-013-9434-1
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    ABSTRACT: Alterations in appetitive processing are central to the major psychological theories of addiction, with differential predictions made by the reward deficiency, incentive salience, and impulsivity hypotheses. Functional MRI has become the chief means of testing these predictions, with experiments reliably highlighting disturbances at the level of the striatum, medial prefrontal cortex, and affiliated regions. However, demonstrations of hypo-reactivity and hyper-reactivity of this circuitry in drug addicted groups are reported in approximately equal measure. Similar findings are echoed in the emergent neuroimaging literature on pathological gambling, which has recently witnessed a coming of age. The first aim of this article is to consider some of the methodological aspects of these experiments that could influence the observed direction of group-level effects, including the baseline condition, trial structure and timing, and the nature of the appetitive cues (drug-related, monetary, or primary rewards). The second aim is to highlight the conceptual traction that is offered by pathological gambling, as a model of a 'toxicity free' addiction and an illness where tasks of monetary reinforcement afford a more direct mapping to the abused commodity. Our conclusion is that relatively subtle decisions in task design appear capable of driving group differences in fronto-striatal circuitry in entirely opposing directions, even with tasks and task variants that look ostensibly similar. Differentiation between the psychological theories of addiction will require a greater breadth of experimental designs, with more research needed on processing of primary appetitive cues, aversive processing, and in vulnerable/at-risk groups.
    03/2013; 2(1):385-393. DOI:10.1016/j.nicl.2013.02.005
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