Transcript Lobo

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.
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 & RihsMiddel, 2007):
PrG: up to 4%
PtG: 0.5 – 2%
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
Comorbidity of
Pathological Gambling
Bipolar
Spectrum
ADHD
Other
Impulse Control
Disorders
Mood Disorders
Personality
Disorders
Compulsive
Sexual Behaviors
PG
Suicide
Substance Use
Disorders
(Potenza, 2002)
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.
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*
WHAT CAN GENES DO?
Genes from the “Mendelian Ages”….
1 gene can fully account for 1 “observable” characteristic
GENOTYPE
PHENOTYPE
DNA = sequence of nucleotides = N base + pentose + phosphate
GENE VARIANTS (alleles, polymorphisms)
CAATGCTTACCGGATCACATAGATATA
SNP (Single Nucleotide Polymorphism):
CAATGCTTACCGGATCACATAGATATA
CAATGCTCACCGGATCACATAGATATA
VNTR (Variable Number of Tandem Repeats):
CAATGCTTACCGGATCACATAGATATA
CAATGCTTACCGGACCGGATCACATAGATATA
CAATGCTTACCGGACCGGACCGGATCACATAGATATA
CAATGCTTACCGGACCGGACCGGACCGGATCACATAGATATA
WHAT CAN GENES DO?
Genes in the “Computer Age”
Microarrays: 1,500,000
Genetic tests in two hours
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.
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
PtG
Controls
Diff.
Increased activation
DLPF cortex in PG
p<0.05
Biol Psychiatry 2005; 58:787-795
TH
phenylalanine
BDNF
dopamine
DAT
MAO-A
COMT
DRD1
DRD2
DRD3
DRD4
DRD5
other genes…
Distribution of Dopamine Receptors - CNS
(Seeman et al., 1995)
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.
Dopamine D1 Receptor Gene Markers
-800 A/G
Prom
1
-48 C/T
Prom
2
+1403 A/G
Coding Region
rs26596 G/T
DRD1 -800 T/C
SNP (Single Nucleotide Polymorphism):
CAATGCTTACCGGATCACATAGATATA
CAATGCTAACCGGATCACATAGATATA
CAATGCTGACCGGATCACATAGATATA
PROMOTER
TIMING, AMOUNT
DRD1 –800 T/C
Alelle
PtG
Sibs
Z
χ2
Exact p
T
80(25%)
27(15%)
2.03
4.15
0.03
C
236(75%) 149(85%)
-2.03
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
MAO –A GENE – X chromosome
Exon 8
rs6323
Promoter
VNTR
Intron 3
rs909525
Intron 2
rs5906957
Intron 11
Rs979606
Intron 12
rs979605
Exon 14
Intron 10
Rs 2205758 rs1801291
Intron 9
rs 3027399
MAO-A VNTR
VNTR (variable number of tandem repeats):
CAATGCTTACCGGATCACATAGATATA
CAATGCTTACCGGATCACATAGATATA
CAATGCTTACCGGACCGGATCACATAGATATA
CAATGCTTACCGGACCGGACCGGATCACATAGATATA
CAATGCTTACCGGACCGGACCGGACCGGATCACATAGATATA
PROMOTER
TIMING, AMOUNT
MAO-A VNTR
130 female PtG x 124 female controls
Control
OR
χ2
p
3/3
18(18%) 15(14%)
2.4
0.84
0.36
3/4
32(33%) 52(48%)
1.2
7.1
0.02
4/4
41(43%) 31(29%) 2.65
4.25
0.03
Genotype
Case
BDNF
rs11030104
val66met
HinfI
rs2049045
rs7103411
BDNF val66met
CAATGCTTACCGGATCACATAGATATA
CAATGCTTACCGGATCACATAGATATA
CAATGCTTACCAGATCACATAGATATA
Change a part of the protein
Alteration in protein structure
BDNF val66met
177 male PtG x 97 male controls
χ2
Alelle
Case
Control
OR
Met
80(25%)
27(15%)
1.87 7.241 0.00712
Val
236(75%) 149(85%)
1
p
Biological Psychiatry, 2007; 61: 911-922
Alberta Cohort Study
N ~ 1000 subjects
Identification of individuals at-risk
Follow up after 5 years
Assessment of gambling behaviour
46%
Genetic
vulnerability
Genes’ variants
PG
+
Life-events
54%
Environment +
Random factors
Exposure to gambling
Winning experiences
(Turner et al.,2002)
TH
phenylalanine
BDNF
dopamine
DAT
MAO-A
COMT
DRD1
DRD2
DRD3
DRD4
DRD5
What can we do?
• Integration of knowledge from different fields
• Vulnerability models and prevention strategies
• Discovery of new drugs for treatment of PG
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