Advancements in the understanding of genetic factors

in problem gambling

Daniela S. S. Lobo, MD, PhD Daniela S. S. Lobo, MD, PhD

Neurogenetics SectionNeurogenetics Section

Centre for Addiction and Mental Centre for Addiction and Mental HealthHealth

Supported by the Ontario Problem Gambling Research Centre -OPGRC, Supported by the Ontario Problem Gambling Research Centre -OPGRC, and the State of São Paulo Research Funding Agency – FAPESP. and the State of São Paulo Research Funding Agency – FAPESP.

• Problem Gamblers (PrG) experience problems with Problem Gamblers (PrG) experience problems with gambling in a less severe degree compared to Pathological gambling in a less severe degree compared to Pathological Gamblers (PtG).Gamblers (PtG).

• Prevalence in adults (Shaffer et al., 2001; Stucki & Rihs-Prevalence in adults (Shaffer et al., 2001; Stucki & Rihs-Middel, 2007): Middel, 2007):

PrG: up to 4%PrG: up to 4%PtG: 0.5 – 2%PtG: 0.5 – 2%

Problem and Pathological GamblingProblem and Pathological Gambling

1/3 PtG are females* (Volberg, 1994; Boughton & Falenchuk, 2007)1/3 PtG are females* (Volberg, 1994; Boughton & Falenchuk, 2007)

Gender differences: gambling styleGender 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 progressionmore rapid progression

Comorbidity of Comorbidity of Pathological GamblingPathological Gambling

PGPG

BipolarBipolarSpectrumSpectrum

Mood DisordersMood Disorders

Personality Personality DisordersDisorders

CompulsiveCompulsiveSexual BehaviorsSexual Behaviors

Substance UseSubstance UseDisordersDisorders

SuicideSuicide

OtherOtherImpulse ControlImpulse Control

DisordersDisorders

ADHDADHD

(Potenza, 2002)(Potenza, 2002)

Family Studies:Family Studies:

• Gambino et al. (1993): risk 12 x for subjects whose parents / Gambino et al. (1993): risk 12 x for subjects whose parents / grandparents were pathological gamblers. grandparents were pathological gamblers.

• Habra et al. (1995), Gupta e Derevensky (1997) Ibañez et al. (2003): Habra et al. (1995), Gupta e Derevensky (1997) Ibañez et al. (2003):

association with familial factors.association with familial factors.

• Black et al. (2005): of 8.3% for PG and 12.4% for any gambling 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 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 FDR of a control group (2.1% for PG and 3.5% for any gambling

disorder).disorder). Higher comorbidity with mood disorders in FDR of PG. Higher comorbidity with mood disorders in FDR of PG.

Genetic Studies and PG:Genetic Studies and PG:

• Winters e Rich (1999): 92 twin pairs – male and high action gamesWinters 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%3359 twin pairs, DZ – 9.8% / MZ – 22.6%

Heritability of 46% for the 4 + symptoms of PG.Heritability of 46% for the 4 + symptoms of PG.

Shared vulnerability : Shared vulnerability : PtG PtG andand Alcohol Dependence, Alcohol Dependence,

Anti-social Personality Anti-social Personality and and Major Depressive Disorder*Major Depressive Disorder*

Twin Studies:Twin Studies:

Genes from the “Mendelian Ages”….Genes from the “Mendelian Ages”….

1 gene can fully account for 1 “observable” characteristic1 gene can fully account for 1 “observable” characteristic

GENOTYPE GENOTYPE PHENOTYPEPHENOTYPE

WHAT CAN GENES DO?WHAT CAN GENES DO?

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

CAATGCTTACCGGATCACATAGATATACAATGCTTACCGGATCACATAGATATA

SNP (SNP (Single Nucleotide PolymorphismSingle Nucleotide Polymorphism):):

CAATGCTCAATGCTTTACCGGATCACATAGATATAACCGGATCACATAGATATA CAATGCTCAATGCTCCACCGGATCACATAGATATAACCGGATCACATAGATATA

VNTR (VNTR (Variable Number of Tandem RepeatsVariable Number of Tandem Repeats):):

CAATGCTTCAATGCTTACCGGACCGGATCACATAGATATAATCACATAGATATACAATGCTTACCGGCAATGCTTACCGGACCGGACCGGATCACATAGATATAATCACATAGATATACAATGCTTACCGGCAATGCTTACCGGACCGGACCGGACCGGACCGGATCACATAGATATAATCACATAGATATACAATGCTTACCGGCAATGCTTACCGGACCGGACCGGACCGGACCGGACCGGACCGGATCACATAGATATA ATCACATAGATATA

GENE VARIANTS (alleles, polymorphisms) GENE VARIANTS (alleles, polymorphisms)

Genes in the “Computer Age”Genes in the “Computer Age”

WHAT CAN GENES DO?WHAT CAN GENES DO?

Microarrays: 1,500,000 Microarrays: 1,500,000 Genetic tests in two hoursGenetic tests in two hours

Large Increase in Genetic Information:Large Increase in Genetic Information:

• DNA chip with 1,000,000 markers now DNA chip with 1,000,000 markers now available to genetic researchersavailable to genetic researchers

• Normal statistics will produce 5% false Normal statistics will produce 5% false positive tests, thus 50,000 positive positive tests, thus 50,000 positive results!results!

• How can we know what markers of the How can we know what markers of the 50,000 are truly linked to the disease?50,000 are truly linked to the disease?

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

Reward System- Olds and Milner, 1954 Reward System- Olds and Milner, 1954

ventral tegmental area, n. accumbens, frontal cortexventral tegmental area, n. accumbens, frontal cortex

DOPAMINE (DA)DOPAMINE (DA) - Accumbens - Accumbens

Unpredictable reward – greater dopamine release – Unpredictable reward – greater dopamine release – behavior maintenancebehavior maintenance

Addictions Immediate RewardAddictions Immediate Reward

DA PATHWAYDA PATHWAY

PtGPtG ControlsControls Diff.Diff.

Biol Psychiatry 2005; 58:787-795Biol Psychiatry 2005; 58:787-795

p<0.05p<0.05

Increased activation Increased activation DLPF cortex in PGDLPF cortex in PG

MAO-AMAO-ACOMTCOMT

DATDAT

DRD1DRD1DRD2DRD2DRD3DRD3DRD4DRD4DRD5DRD5

THTH

phenylalaninephenylalanine dopaminedopamine

BDNFBDNF

other genes…other genes…

Distribution of Dopamine Receptors - CNSDistribution of Dopamine Receptors - CNS

(Seeman et al., 1995)(Seeman et al., 1995)

Methods:Methods:

•PG seeking treatmentPG seeking treatment

• 140 sib-pairs interviewed: PG and one non-gambler 140 sib-pairs interviewed: PG and one non-gambler sibling, age difference below 5 years. sibling, age difference below 5 years.

• Pathological Gambling diagnosis: DSM-IV and SOGSPathological Gambling diagnosis: DSM-IV and SOGS

• Temperament and Character Inventory - TCI Temperament and Character Inventory - TCI (Cloninger,1993) and Barrat Impulsiveness Scale - BIS (Cloninger,1993) and Barrat Impulsiveness Scale - BIS (Patton and Barrat, 1995).(Patton and Barrat, 1995).

• Psychiatric Comorbidity: SCAN.Psychiatric Comorbidity: SCAN.

Dopamine D1 Receptor Gene MarkersDopamine D1 Receptor Gene Markers

Coding RegionCoding Region

-800 A/G-800 A/G -48 C/T-48 C/T +1403 A/G+1403 A/G

PromProm11

PromProm22

rs26596 G/Trs26596 G/T

DRD1 -800 T/CDRD1 -800 T/C

SNP (SNP (Single Nucleotide PolymorphismSingle Nucleotide Polymorphism):):CAATGCTTACCGGATCACATAGATATACAATGCTTACCGGATCACATAGATATA

CAATGCTCAATGCTAAACCGGATCACATAGATATAACCGGATCACATAGATATA CAATGCTCAATGCTGGACCGGATCACATAGATATAACCGGATCACATAGATATA

PROMOTERPROMOTER TIMING, AMOUNTTIMING, AMOUNT

AlelleAlelle PtGPtG SibsSibs ZZ χχ22 Exact pExact p

TT 80(2580(25%%)) 27(1527(15%%)) 2.032.03 4.154.15 0.030.03

CC 236(75236(75%%)) 149(85149(85%%)) -2.03-2.03

DRD1 –800 T/CDRD1 –800 T/C

CAMH Problem Gambling StudyCAMH 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 TestThe 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 ADHDThe Wender Utah Rating Scale (WURS) for ADHD

• ALBERTA COHORT STUDYALBERTA COHORT STUDY

PromoterPromoter VNTRVNTR

Intron 2Intron 2rs5906957rs5906957

Intron 3Intron 3rs909525rs909525

Exon 8 Exon 8 rs6323rs6323

Intron 9Intron 9rs 3027399rs 3027399

Intron 10Intron 10Rs 2205758Rs 2205758

Intron 11Intron 11Rs979606Rs979606Intron 12Intron 12rs979605rs979605

Exon 14Exon 14rs1801291rs1801291

MAO –A GENE – X chromosomeMAO –A GENE – X chromosome

VNTR (VNTR (variable number of tandem repeatsvariable number of tandem repeats):):

CAATGCTTACCGGATCACATAGATATACAATGCTTACCGGATCACATAGATATA

CAATGCTTCAATGCTTACCGGACCGGATCACATAGATATAATCACATAGATATACAATGCTTACCGGCAATGCTTACCGGACCGGACCGGATCACATAGATATAATCACATAGATATA

CAATGCTTACCGGCAATGCTTACCGGACCGGACCGGACCGGACCGGATCACATAGATATAATCACATAGATATACAATGCTTACCGGCAATGCTTACCGGACCGGACCGGACCGGACCGGACCGGACCGGATCACATAGATATAATCACATAGATATA

PROMOTERPROMOTER TIMING, AMOUNTTIMING, AMOUNT

MAO-A VNTRMAO-A VNTR

MAO-A VNTRMAO-A VNTR

GenotypeGenotype CaseCase ControlControl OROR χχ22 pp

3/33/3 18(1818(18%%)) 15(1415(14%%)) 2.42.4 0.840.84 0.360.36

3/43/4 32(3332(33%%)) 52(4852(48%%)) 1.21.2 7.17.1 0.020.02

4/44/4 41(4341(43%%)) 31(2931(29%%)) 2.652.65 4.254.25 0.030.03

130 female PtG x 124 female controls130 female PtG x 124 female controls

BDNFBDNF

val66metval66met HinfIHinfI

rs11030104rs11030104

rs2049045rs2049045

rs7103411rs7103411

BDNF val66metBDNF val66met

CAATGCTTACCGGATCACATAGATATACAATGCTTACCGGATCACATAGATATA

CAATGCTTACCCAATGCTTACCGGGATCACATAGATATAGATCACATAGATATA

CAATGCTTACCCAATGCTTACCAAGATCACATAGATATAGATCACATAGATATA

Change a part of the proteinChange a part of the protein

Alteration in protein structure Alteration in protein structure

BDNF val66metBDNF val66met

AlelleAlelle CaseCase ControlControl OROR χχ22 pp

MetMet 80(2580(25%%)) 27(1527(15%%)) 1.871.87 7.2417.241 0.007120.00712

ValVal 236(75236(75%%)) 149(85149(85%%)) 11

177 male PtG x 97 male controls177 male PtG x 97 male controls

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

N ~ 1000 subjectsN ~ 1000 subjects

Identification of individuals at-riskIdentification of individuals at-risk

Follow up after 5 yearsFollow up after 5 years

Assessment of gambling behaviourAssessment of gambling behaviour

Alberta Cohort StudyAlberta Cohort Study

46%46%GeneticGenetic

vulnerabilityvulnerability

54% 54% Environment + Environment + Random factorsRandom factors

PGPG++Life-eventsLife-events

Exposure to gamblingExposure to gambling

Winning experiencesWinning experiences

(Turner et al.,2002)(Turner et al.,2002)

Genes’ variantsGenes’ variants

MAO-AMAO-ACOMTCOMT

DATDAT

DRD1DRD1DRD2DRD2DRD3DRD3DRD4DRD4DRD5DRD5

THTH

phenylalaninephenylalanine dopaminedopamine

BDNFBDNF

What can we do?What can we do?

• Integration of knowledge from different fields Integration of knowledge from different fields

• Vulnerability models and prevention strategiesVulnerability models and prevention strategies

• Discovery of new drugs for treatment of PGDiscovery of new drugs for treatment of PG

THANKS!THANKS!

Neurogenetics Laboratory - CAMHNeurogenetics Laboratory - CAMHDr. James KennedyDr. James Kennedy

Nicole KingNicole KingSahar EhteshamSahar Ehtesham

Joanne BrathwaiteJoanne BrathwaiteOlga LikohdiOlga Likohdi

Institute of Psychiatry – University of Institute of Psychiatry – University of SSãão Pauloo Paulo

PROGENE – Psychiatric Genetic PROGENE – Psychiatric Genetic

LaboratoryLaboratory

AMJO – Gambling Outpatient UnitAMJO – Gambling Outpatient Unit