Advancements in the understanding of genetic factors in problem gambling

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 and Pathological Gambling • 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): • PrG: up to 4% • PtG: 0.5 – 2%

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

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

5. Genetic Studies and PG: • Family Studies: • 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. • 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.

6. Twin Studies: • Winters e Rich (1999): 92 twin pairs – male and high action games • No evaluation of problem/ pathological gambling. • 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, • Anti-social Personality and Major Depressive Disorder*

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

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

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

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

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 researchers • 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? • Need guidance from clinical and neurobiological information.

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

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

18. TH phenylalanine dopamine BDNF DAT MAO-A COMT DRD1 DRD2 DRD3 DRD4 DRD5 other genes…

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

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

22. Prom1 Dopamine D1 Receptor Gene Markers -800 A/G -48 C/T +1403 A/G Prom2 Coding Region rs26596 G/T

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

24. DRD1 –800 T/C

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

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

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

28. MAO-A VNTR 130 female PtG x 124 female controls

29. BDNF rs7103411 rs11030104 HinfI val66met rs2049045

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

31. BDNF val66met 177 male PtG x 97 male controls

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

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

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

35. TH phenylalanine dopamine BDNF DAT MAO-A COMT DRD1 DRD2 DRD3 DRD4 DRD5

36. What can we do? • Integration of knowledge from different fields • Vulnerability models and prevention strategies • 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