1. Advancements in the understanding of genetic factors in problem gambling Daniela S. S. Lobo, MD, PhD Neurogenetics Section Centre for Addiction and Mental Health Supported by the Ontario Problem Gambling Research Centre -OPGRC, and the State of São Paulo Research Funding Agency – FAPESP.

2. Problem Gamblers (PrG) experience problems with gambling in a less severe degree compared to Pathological Gamblers (PtG). Problem Gamblers (PrG) experience problems with gambling in a less severe degree compared to Pathological Gamblers (PtG). Prevalence in adults (Shaffer et al., 2001; Stucki & Rihs- Middel, 2007): Prevalence in adults (Shaffer et al., 2001; Stucki & Rihs- Middel, 2007): PrG: up to 4% PtG: 0.5 – 2% Problem and Pathological Gambling

3. 1/3 PtG are females* (Volberg, 1994; Boughton & Falenchuk, 2007) Gender differences: gambling style different gambling activities different gambling activities “gambling to escape feelings of guilt and depression” “gambling to escape feelings of guilt and depression” more rapid progression more rapid progression

4. Comorbidity of Pathological Gambling PG BipolarSpectrum Mood Disorders PersonalityDisorders Compulsive Sexual Behaviors Substance Use Disorders Suicide Other Impulse Control Disorders ADHD (Potenza, 2002)

5. Family Studies: Gambino et al. (1993): risk 12 x for subjects whose parents / grandparents were pathological gamblers. Gambino et al. (1993): risk 12 x for subjects whose parents / grandparents were pathological gamblers. Habra et al. (1995), Gupta e Derevensky (1997) Ibañez et al. (2003): association with familial factors. Habra et al. (1995), Gupta e Derevensky (1997) Ibañez et al. (2003): association with familial factors. Black et al. (2005): of 8.3% for PG and 12.4% for any gambling disorder among FDR of PG. Significantly higher when compared to FDR of a control group (2.1% for PG and 3.5% for any gambling disorder). Higher comorbidity with mood disorders in FDR of PG. Black et al. (2005): of 8.3% for PG and 12.4% for any gambling disorder among FDR of PG. Significantly higher when compared to FDR of a control group (2.1% for PG and 3.5% for any gambling disorder). Higher comorbidity with mood disorders in FDR of PG. Genetic Studies and PG:

6. Winters e Rich (1999): 92 twin pairs – male and high action games Winters e Rich (1999): 92 twin pairs – male and high action games No evaluation of problem/ pathological gambling. No evaluation of problem/ pathological gambling. Eisen et al. (1998); Slutske et al. (2000); Potenza et al. (2005): Eisen et al. (1998); Slutske et al. (2000); Potenza et al. (2005): 3359 twin pairs, DZ – 9.8% / MZ – 22.6% Heritability of 46% for the 4 + symptoms of PG. Shared vulnerability : PtG and Alcohol Dependence, Shared vulnerability : PtG and Alcohol Dependence, Anti-social Personality and Major Depressive Disorder* Anti-social Personality and Major Depressive Disorder* Twin Studies:

7. Genes from the “Mendelian Ages”…. 1 gene can fully account for 1 “observable” characteristic GENOTYPE PHENOTYPE WHAT CAN GENES DO?

10. DNA = sequence of nucleotides = N base + pentose + phosphate

11. CAATGCTTACCGGATCACATAGATATA SNP (Single Nucleotide Polymorphism): SNP (Single Nucleotide Polymorphism): CAATGCTTACCGGATCACATAGATATA CAATGCTTACCGGATCACATAGATATA CAATGCTCACCGGATCACATAGATATA CAATGCTCACCGGATCACATAGATATA VNTR (Variable Number of Tandem Repeats): VNTR (Variable Number of Tandem Repeats): CAATGCTTACCGGATCACATAGATATA CAATGCTTACCGGACCGGATCACATAGATATA CAATGCTTACCGGACCGGACCGGATCACATAGATATA CAATGCTTACCGGACCGGACCGGACCGGATCACATAGATATA GENE VARIANTS (alleles, polymorphisms)

13. Genes in the “Computer Age” WHAT CAN GENES DO?

14. Microarrays: 1,500,000 Genetic tests in two hours

15. Large Increase in Genetic Information: DNA chip with 1,000,000 markers now available to genetic researchersDNA chip with 1,000,000 markers now available to genetic researchers Normal statistics will produce 5% false positive tests, thus 50,000 positive results!Normal statistics will produce 5% false positive tests, thus 50,000 positive results! How can we know what markers of the 50,000 are truly linked to the disease?How can we know what markers of the 50,000 are truly linked to the disease? Need guidance from clinical and neurobiological information.Need guidance from clinical and neurobiological information.

16. Reward System- Olds and Milner, 1954 ventral tegmental area, n. accumbens, frontal cortex DOPAMINE (DA) - Accumbens Unpredictable reward – greater dopamine release – behavior maintenance Addictions Immediate Reward Addictions Immediate Reward DA PATHWAY

17. PtGControlsDiff. Biol Psychiatry 2005; 58:787-795 p<0.05 Increased activation Increased activation DLPF cortex in PG

18. MAO-ACOMT DAT DRD1DRD2DRD3DRD4DRD5THphenylalanine dopamine BDNF other genes…

19. Distribution of Dopamine Receptors - CNS (Seeman et al., 1995)

21. Methods: PG seeking treatmentPG seeking treatment 140 sib-pairs interviewed: PG and one non-gambler sibling, age difference below 5 years. 140 sib-pairs interviewed: PG and one non-gambler sibling, age difference below 5 years. Pathological Gambling diagnosis: DSM-IV and SOGS Pathological Gambling diagnosis: DSM-IV and SOGS Temperament and Character Inventory - TCI (Cloninger,1993) and Barrat Impulsiveness Scale - BIS (Patton and Barrat, 1995). Temperament and Character Inventory - TCI (Cloninger,1993) and Barrat Impulsiveness Scale - BIS (Patton and Barrat, 1995). Psychiatric Comorbidity: SCAN. Psychiatric Comorbidity: SCAN.

22. Dopamine D1 Receptor Gene Markers Coding Region -800 A/G -48 C/T +1403 A/G Prom 1 Prom 2 rs26596 G/T

23. DRD1 -800 T/C SNP (Single Nucleotide Polymorphism): CAATGCTTACCGGATCACATAGATATA CAATGCTAACCGGATCACATAGATATA CAATGCTAACCGGATCACATAGATATA CAATGCTGACCGGATCACATAGATATA CAATGCTGACCGGATCACATAGATATA PROMOTER TIMING, AMOUNT PROMOTER TIMING, AMOUNT

24. AlellePtGSibsZ χ2χ2χ2χ2 Exact p T 80(25 % ) 27(15 % ) 2.034.150.03 C 236(75 % ) 149(85 % ) -2.03 DRD1 –800 T/C

25. CAMH Problem Gambling Study DSM-IV for problem gambling (self-report version)DSM-IV for problem gambling (self-report version) South Oaks Gambling Screen (SOGS) South Oaks Gambling Screen (SOGS) The Random Events Knowledge Test The Random Events Knowledge Test Gambling Cognition Questionnaire (GCQ) Gambling Cognition Questionnaire (GCQ) The Temperament and Character Inventory (TCI) The Temperament and Character Inventory (TCI) Stopsignal Paradigm Test (SSPT) Stopsignal Paradigm Test (SSPT) The Wender Utah Rating Scale (WURS) for ADHD The Wender Utah Rating Scale (WURS) for ADHD ALBERTA COHORT STUDY ALBERTA COHORT STUDY

26. Promoter VNTR VNTR Intron 2 rs5906957 Intron 3 rs909525 Exon 8 rs6323 Intron 9 rs 3027399 Intron 10 Rs 2205758 Intron 11 Rs979606 Intron 12 rs979605 Exon 14 rs1801291 MAO –A GENE – X chromosome

27. VNTR (variable number of tandem repeats): CAATGCTTACCGGATCACATAGATATA CAATGCTTACCGGATCACATAGATATA CAATGCTTACCGGACCGGATCACATAGATATA CAATGCTTACCGGACCGGACCGGATCACATAGATATA CAATGCTTACCGGACCGGACCGGACCGGATCACATAGATATA PROMOTER TIMING, AMOUNT MAO-A VNTR

28. GenotypeCaseControlOR χ2χ2χ2χ2p 3/3 18(18 % ) 15(14 % ) 2.40.840.36 3/4 32(33 % ) 52(48 % ) 1.27.10.02 4/4 41(43 % ) 31(29 % ) 2.654.250.03 130 female PtG x 124 female controls

29. BDNF val66met HinfI rs11030104 rs2049045 rs7103411

30. BDNF val66met CAATGCTTACCGGATCACATAGATATA CAATGCTTACCGGATCACATAGATATA CAATGCTTACCAGATCACATAGATATA Change a part of the protein Alteration in protein structure

31. BDNF val66met AlelleCaseControlOR χ2χ2χ2χ2p Met 80(25 % ) 27(15 % ) 1.877.2410.00712 Val 236(75 % ) 149(85 % ) 1 177 male PtG x 97 male controls

32. Biological Psychiatry, 2007; 61: 911-922

33. N ~ 1000 subjects Identification of individuals at-risk Follow up after 5 years Assessment of gambling behaviour Alberta Cohort Study

34. 46%Geneticvulnerability 54% Environment + Random factors PG + Life-events Exposure to gambling Winning experiences (Turner et al.,2002) Genes’ variants

35. MAO-ACOMT DAT DRD1DRD2DRD3DRD4DRD5THphenylalanine dopamine BDNF

36. What can we do? Integration of knowledge from different fields Integration of knowledge from different fields Vulnerability models and prevention strategies Vulnerability models and prevention strategies Discovery of new drugs for treatment of PG Discovery of new drugs for treatment of PG

37. THANKS! Neurogenetics Laboratory - CAMH Dr. James Kennedy Nicole King Sahar Ehtesham Joanne Brathwaite Olga Likohdi Institute of Psychiatry – University of São Paulo PROGENE – Psychiatric Genetic Laboratory AMJO – Gambling Outpatient Unit