Genes that affect novelty seeking behavior

1. Genes that affect novelty seeking behavior

2. Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. • Richard Ebstein et al., 1996

3. The tridimensional personality questionnaire (TPQ) • Designed to measure aspects of temperament: • Novelty Seeking • Harm Avoidance • Reward Dependence • Persistence

4. 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)

5. High score on the Novelty Seeking scale: • impulsive, exploratory, fickle, excitable, quick-tempered, extravagant • Low score on the Novelty Seeking scale: • reflective, rigid, loyal, stoic, slow-tempered, frugal

6. From earlier work, Cloninger proposed that individual differences in Novelty Seeking were associated with genetic differences related to the neurotransmitter dopamine and its receptors.

7. 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.

8. Dopamine mediates exploratory behavior in experimental animals. • The rewarding effects of amphetamines and cocaine are related to dopamine release. • Novelty Seeking is low in dopamine-deficient patients with Parkinson's disease.

9. 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

10. 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).

11. Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking. • Jonathan Benjamin, et al., 1996 • Dean Hamer lab, NIH

12. 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.

13. 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.

14. 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).

15. 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.

16. 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).

17. 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.

18. 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)

19. Conclusion • Differences in Novelty Seeking between individuals are significantly associated with difference in the D4 dopamine receptor gene.

20. 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.

21. 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.

22. No association between dopamine D4 receptor gene exon III and -521C/T polymorphism and Novelty Seeking • A. Strobel et al. 2002

23. 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?

24. 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.

25. 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

26. Results • Individuals with or without the D4DR exon III 7-repeat 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.

27. Possible reasons for lack of associations between D4DR polymorphisms and Novelty Seeking.

28. 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.

29. Further evidence for a modulation of Novelty Seeking by DRD4 exon III, 5-HTTLPR and COMT val/met variants. • A. Strobel et al. 2003 • (Same group as prior report)

30. 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.

31. 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".

32. 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.

33. 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.

34. 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.