Lobo AGRI Conference 2010 by WhiONJZ

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									     Functional variants in the dopamine
     D2-like receptors are associated with
     lower risk for gambling behaviour in
          healthy Caucasian subjects

 Daniela S. S. Lobo M.D., Ph.D , Renan P. Souza Ph.D., Ryan P. Tong
 B.Sc., David M. Casey Ph.D., David C. Hodgins Ph.D., Garry J. Smith
 Ph.D., Rob J. Williams Ph.D., Don P. Schopflocher Ph.D., Rob T. Wood
 Ph.D., Nady el-Guebaly M.D., James L. Kennedy M.D.


     Neurogenetics Section, Problem Gambling Service
Centre for Addiction and Mental Health - University of Toronto
       Pathological Gambling - Phenotype


• behavioural addiction (Marks, 1990)
• high impulsive traits
• high comorbidity rates


• degrees of severity – continuum (Eisen et al., 1998, 2001)
   • 3-4 DSM criteria = Problem Gambling (~6%)
   •  5 DSM criteria = Pathological Gambling (~2%)
Why Dopamine Receptor Genes?
 Dopamine Receptors and Reward Mechanisms

• Two types of Dopamine (DA) receptors

   • D1- like: DRD1 and DRD5
   • D2-like: DRD2, DRD3, DRD4


• DA is the main neurotransmitter involved in substance
and behavioural addictions

• Changes in DA receptors in the brain have been observed
through imaging techniques in individuals who have
addictive disorders.
                Objectives


• To evaluate whether genetic variants in the
dopaminergic receptors could be used as
susceptibility markers of gambling behaviour in
healthy subjects using the Problem Gambling
Severity Index (PGSI) derived from the Canadian
Problem Gambling Index (CPGI).
                     Methods
• Sample
   • Lifestyle, and Lifecycle Project
   • First wave of data collection: 1,372 adult subjects
   were assessed, with 325 subjects providing consent
   to participate in the genetic arm of the study
   • Only Caucasians included (242 subjects)


• Assessment (instruments used in this study)
   • CIDI
   • CPGI
   • Demographic data
                    Methods
• Genotyping:

•The TaqIA/rs1800497 alters D2 receptor density
(Jonsson et al., 1999;Neville et al., 2004).
• Located in the ankyrin repeat and kinase domain
containing 1 gene (ANKK1) (Neville et al., 2004).
• Two other functional variants in the DRD2 gene (BstNI/
rs1799732 and C957T/ rs6277) have been reported to
affect D2 receptor availability (Hirvonen et al., 2009a;
Hirvonen et al., 2009b; Jonsson et al., 1999).

•The DRD3 rs6280 (Ser9Gly). The Gly9 variant presents
increased dopamine affinity – “gain-of function effect”
                          Methods


• Statistical Analysis:
   • General Linear Model with and without covariates
   • Analysis of combined variants of genes (haplotypes)
   • Estimate of sample power:
       • 94% power to detect PGSI variations as low as 0.45
        assuming that genetic variations account for 5% of
        the variance in PGSI scores
                        Results

• Final sample: 242 subjects (PGSI 0-7)
   • 90 males + 152 females
   • Mean PGSI score = 0.53 ± 1.18
   • Mean Age = 46.6 ± 16 years

• Gender: PGSI scores not significantly different

• Younger age associated with higher PGSI scores
                       Results


• DRD3 MscI/ rs6280 – Ser9 allele
  • P = 0.03
  • corrected by age P = 0.01, F = 3.629, R2 = 0.05


   Subjects with this variant have lower PGSI.
Results

  • Association (p= 0.005) of the
  haplotype with lower PGSI
  scores in healthy subjects


       rs11604671 – G or A

       rs4938015 – C or T

       rs2303380 – A or G
                      Discussion


• Comings et al. (Comings et al., 1996) reported
  association of PG with allele T of TaqIA/ rs1800497;

• More recent studies suggest that variants on ANKK1 and
  NOT the TaqIA are associated with addictive disorders
  (Gerlernter et al., 2006, Yang et al., 2008)

• Haplotype composed by the opposite alleles in the same
  three variants (rs11604671-rs4938015-rs2303380) have
  been associated with increased risk for nicotine
  dependence in two populations (Gerlernter et al., 2006)
                  Discussion
          From a clinical standpoint…

• Symptoms of PG fluctuate over time and several
  questions remain as to whether individuals with
  subclinical levels of PG will present a higher rate of
  progression to PG compared to non-gamblers (LaPlante
  et al., 2008), which can be influenced by numerous
  environmental factors such as availability of gambling
  venues, and significant life-events that could promote
  behavioural change.
                 Discussion
        From a biological standpoint…


• Subjects who gamble at least 25 times in a year
  but have never developed any symptoms of PG
  genetic factors account for 35% of the variance

• Subjects with 1, 2, or 3 symptoms of PG in their
  lifetime - contribution of genetic factors is
  estimated to be 48%, 54%, and 67%
  respectively (Eisen et al., 1998).
     From a clinical and biological
              standpoint
• Genes are not single determinants of
  human behaviours. Genes can contribute
  to traits that will influence human
  behaviour.

• We only evaluated the genetic risk
  component of the gene-environment
  interplay
                Acknowledgments
                     Natalie Freeman
                     Olga Likhodi
                     Maria Tampakeras

       Ontario Problem Gambling Research Centre
(“Factors influencing the development of responsible gaming”),
            Alberta Gaming Research Institute
           (“Leisure, Lifestyle, Lifecycle Project”),
          Canadian Institutes of Health Research
     (RPS is holder of Postdoctoral Fellowship #93967).

								
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