Transcript Genes that affect novelty seeking behavior

Genes that affect novelty
seeking behavior
• Dopamine D4 receptor (D4DR) exon III
polymorphism associated with the human
personality trait of Novelty Seeking.
• Richard Ebstein et al., 1996
The tridimensional personality
questionnaire (TPQ)
• Designed to measure aspects of
temperament:
– Novelty Seeking
– Harm Avoidance
– Reward Dependence
– Persistence
TPQ example Novelty Seeking
questions
• True / False
• I often try new things just for fun or thrills,
even if most people think it is a waste of
time. (T)
• I often do things based on how I feel at the
moment without thinking about how they
were done in the past. (T)
• I am much more controlled than most
people. (F)
• High score on the Novelty Seeking scale:
– impulsive, exploratory, fickle, excitable, quicktempered, extravagant
• Low score on the Novelty Seeking scale:
– reflective, rigid, loyal, stoic, slow-tempered,
frugal
• From earlier work, Cloninger proposed
that individual differences in Novelty
Seeking were associated with genetic
differences related to the neurotransmitter
dopamine and its receptors.
• Evidence suggesting that dopamine, and
particularly D4DR polymorphisms, are
related to Novelty Seeking
• Studies have shown that the number of
exon III repeats can affect the affinity of
ligand (proteins or drugs) that bind to the
receptor.
• D4DR is expressed in limbic areas
involved in cognition and emotion.
• Dopamine mediates exploratory behavior
in experimental animals.
• The rewarding effects of amphetamines
and cocaine are related to dopamine
release.
• Novelty Seeking is low in dopaminedeficient patients with Parkinson's disease.
Methods
• 124 Israeli normal adult male and female
volunteers
• Determined length of the D4DR exon III repeat
sequences
• Found that the most frequent alleles were the 4
repeat and the 7 repeat
• Genotypes divided into two groups:
– those containing two copies of the 4 repeat
– those containing one 4 repeat and the 7 repeat
Results
• Subjects with the 7-repeat allele had significantly
higher Novelty Seeking scores than did subjects
lacking the 7-repeat allele. p = 0.013.
• No significant differences between the groups
for:
– Harm Avoidance
– Reward Dependence
– Persistence
• No significant differences in Novelty Seeking
due to ethnicity, age or sex (but trend for decline
with age).
• Population and familial association
between the D4 dopamine receptor gene
and measures of Novelty Seeking.
• Jonathan Benjamin, et al., 1996
• Dean Hamer lab, NIH
• Twin and adoption studies suggest that 30 to 60% of the
variance in many personality traits is due to inherited
factors.
• However, little is known about the genes involved, how
they differ between people.
• Little is known about how the genes interact with the
developing brain and with environmental and
experiential factors to generate behavior.
• Ebstein et al found a population association between a
long allele of polymorphic exon III repeat sequence of
the D4 dopamine receptor gene (D4DR) and the normal
personality trait of Novelty Seeking.
Hamer et al used the NEO
personality inventory
•
•
•
•
high retest reliability
longitudinal stability
validated in many populations and cultures
good correlation between self reports and
observer ratings.
• NEO does not include Novelty Seeking as a
specific factor, but it contains items clearly
related to questions from the TPQ- Novelty
Seeking Scale:
– "I have sometimes done things just for kicks or thrills"
vs. "I often try new things just for fun or thrills"
– "I think things through before coming to a decision"
vs. "I like to think about things for a long time before I
make a decision"
• Empirical studies show 70% correlation between
TPQ- Novelty Seeking and certain NEO factors
(positive correlation with Extraversion, negative
with Conscientiousness).
• Hamer et al hypothesis:
• Long alleles of D4DR exon III are
positively associated with NEO
Extraversion, negatively associated with
NEO Conscientiousness, and positively
associated with TPQ- Novelty Seeking as
estimated from the NEO questions.
Methods
• Determined length of the D4DR exon III repeate
sequences for 315 volunteers
• Genotypes divided into two groups:
– those containing only the short (S) D4DR allele with 2
to 5 exon III repeats (n=217)
– those containing one or two copies of the long (L)
allele with 6 to 8 exon III repeats (n=98)
• Personality scores were statistically corrected for
age, sex, ethnicity, and sexual orientation (all of
which affect the scores in a relatively consistent
way).
Results
• Scores for Extraversion were higher in L
than in S subjects (p=0.001)
• Scores for Conscientiousness were lower
in L than in S subjects (p=0.03)
• The other 3 NEW personality factors were
not significantly associated.
• Hamer et al performed a second study using 60
pairs of siblings
• In each pair, one sib had the long genotype (L)
and one had the short genotype (S)
• The results were the same as for the population
study:
– Scores for Extraversion were higher in L than in S
subjects (p=0.001)
– Scores for Conscientiousness were lower in L than in
S subjects (p=0.03)
Conclusion
• Differences in Novelty Seeking between
individuals are significantly associated with
difference in the D4 dopamine receptor
gene.
Discussion
• In these two studies, D4DR accounts for only 3
to 4% of the total variability in Novelty Seeking.
• Heritability of Novelty Seeking, based on twin
studies, is estimated to be about 41%.
• Thus, D4DR accounts for roughly 41/4 = 10% of
the genetic variance.
• These results suggest that Novelty Seeking is
partially but not completely mediated by genes,
and that the D4DR polymorphism accounts for
some but not all of the genetic effects.
• These results confirm and extend those of
Ebstein et al.
• The great differences in populations
supports the result: Israeli Jews vs.
predominantly non-Jewish Caucasians
with some Hispanic, Asian and African
American from the U.S.
• No association between dopamine D4
receptor gene exon III and -521C/T
polymorphism and Novelty Seeking
• A. Strobel et al. 2002
• Reports from several groups (including these
authors) gave evidence for an association
between D4DR and Novelty Seeking
• However, some studies have failed to replicate
the initial findings.
• Were the early results just due to chance results
in small or unusual populations, and not a real
effect of D4DR, or not representative of the
general population?
• A single nucleotide polymorphism (SNP) in
the promoter region (-521C/T ) of the
D4DR gene had also been reported to be
associated with differences in Novelty
Seeking.
• Strobel et al decided to study a German
population to see if the D4DR exon III
repeat or -521C/T were associated with
Novelty Seeking.
Methods
• 276 unrelated healthy volunteers of
German ethnicity
• 205 women, 71 men
• mean age 22 years, age range 18 – 41
years
• German version of TPQ
• Determined D4DR genotypes
Results
• Individuals with or without the D4DR exon III 7repeat showed no significant differences in their
Novelty Seeking scores (p = 0.26).
• Individuals with or without the SNP in the
promoter region (-521C/T ) showed no
significant differences in their Novelty Seeking
scores (p = 0.74).
• No differences were observed in several
analyses of alternative groupings.
• Possible reasons for lack of associations
between D4DR polymorphisms and
Novelty Seeking.
• Sample may not have provided sufficient power
(small sample size) to detect association.
However, their sample size was greater than that
of prior studies.
• Unknown ethnic stratification may have given a
false negative result. But all participants were
ethnic Germans.
• Developmental factors and compensatory
interactions with other biological mechanisms
may account for the presence or absence of a
phenotypic effect of a functional polymorphism.
• Further evidence for a modulation of
Novelty Seeking by DRD4 exon III, 5HTTLPR and COMT val/met variants.
• A. Strobel et al. 2003
– (Same group as prior report)
• Benjamin et al. had found:
– Novelty Seeking scores are higher in the
presence of the DRD4 exon III 7-repeat allele
in the absence of the short (s) allele of the
serotonin transporter gene promoter-linked
polymorphic region (5-HTTLPR) and in the
presence of the val/met genotype of the
COMT gene.
• Benjamin suggested "that failure to
replicate associations between personality
factors and some genes may be partially
due to the presence of additional
modifying common polymorphisms".
• Strobel et al. decided to see if this effect
explained their failure to find an
association in their German population.
• Genotyped 5-HTTLPR and COMT val/met
in their prior subjects.
Hypothesis
• In the group defined by 5-HTTLPR 1/1
genotype and COMT val/val genotype,
individuals with the DRD4 exon III 7-repeat
allele would have higher Novelty Seeking
scores than those without the repeat.
Results
• Found a significant difference between those
with and without the 7-repeat allele, p = 0.035
after accounting for differences in the other
polymorphisms.
• The study shows that the failure to detect an
effect (due to D4DR polymorphisms) could be
explained by the presence of additional
modifying common polymorphisms.
• Inclusion of additional genetic variations may
help resolve some of the inconsistencies in
human gene-personality/behavior correlation
studies.