Decision-making behaviour is influenced by tryptophan hydroxylase 2 gene

Introduction: Tryptophan hydroxylase (TPH) is the rate-limiting
enzyme in the synthesis of the neurotransmitter serotonin (5-HT).
There are two main subtypes, the TPH2 subtype which is involved
in neuronal serotonin synthesis and the TPH1 subtype which is
involved in serotonin synthesis in the periphery. Polymorphisms in
the TPH2 gene and distinct haplotypes (combinations of single nucleotide
polymorphisms (SNPs) which are inherited together) with
functional effects on the TPH enzyme activity may represent risk
factors for serotonergic system related psychiatric disorders. However,
genetic studies of TPH2 related to depression, schizophrenia,
alcoholism, drug abuse, aggression and suicidality have produced
conflicting results. One possible explanation of this is that TPH2
function might relate to a more basic behavioural feature, or
endophenotype, involved in many psychiatric disorders. Decision
making may be defined as the ability to select an advantageous
response from a range of available options. Impaired decision
making, attributed to a 5-HT deficit in orbitofrontal cortex (OFC),
is one candidate endophenotype for many psychiatric conditions.
Previous studies demonstrated that rapid dietary tryptophan depletion
– leading to reduced central serotonin function – altered
the decision-making of healthy volunteers. In our study, we tested
the hypothesis that TPH2 haplotype will affect decision making,
in a large sample using a simple paper-pencil task.
Methods: From the NewMood population study cohort we
present interim data on 864 subjects who completed a pencil
and paper decision making task, the 53-item Brief Symptom
Checklist and for whom we have TPH2 genetic haplotype data.
The task consisted of choosing between two ‘wheel of fortunelike’
alternatives: ‘A’ which provided a smaller but more likely
‘win’ and ‘B’ which gave a ‘win’ 2 times the amount with lower
probability that was systematically varied. We used a repeated
measure design with 4 different probability levels of winning on
‘A’. The probability of winning on ‘B’ at which the subjects valued
the two trials equally (indifference point) was determined as a
measure of willingness to take a risk. The HaploView software
package was employed to identify htSNPs based on the genotype
data of CEPH population (International HapMap Project).
The chosen SNPs were genotyped using Sequenom’s massarray
technology and haplotypes were generated by HelixTree.
Results: TPH2 haplotypes (p = 0.003) and Anxiety scores
(p = 0.001) had an independent significant effect on decision
making, with more anxious subjects making less risky choices.
There was no interaction between TPH2 haplotypes and Anxiety
scores. Depression scores had no effect on decision making.
Discussion: This study supports the role of TPH2 gene, and
the 5-HT system, in risk taking behaviour. This genetic effect
is independent of mood state and might be an additive factor
contributing to psychiatric disorders.