Each year, one million people die of suicide. Polymorphisms of genes can contribute to alterations in protein function in vivo, and twin and adoption family studies have provided evidence for familial transmission in suicide.33,34
The association of lower serotonergic function and suicidal behaviour indicate that genes related to the serotonergic system are candidates worthy of study as part of the genetic diathesis for suicidal behaviour. Tryptophan hydroxylase (TPH) catalyses the 5‐hydroxylation of tryptophan, which is the first step in the biosynthesis of indoleamines (serotonin and melatonin).4
Nielsen found the TPH genotype to be significantly associated with cerebrospinal fluid 5‐hydroxyindoleacetic acid (5‐HIAA) concentration in subjects suffering from impulsive behaviour. A genetic variant of the TPH gene has also been associated with violent suicide attempts. It may influence 5‐HIAA concentration in the cerebrospinal fluid and produce a predisposition to suicidal behaviour.3
Neurobiological studies also implicate serotonergic dysfunction in suicidal behaviour. Because genetic variants in the human TPH1 promoter and intron 7 can modulate gene transcription, these two loci have been widely studied in the TPH
gene, but results have been mixed. Rujescu has provided strong evidence for an association of suicide related behaviour with A218 in TPH
in a meta‐analysis.2
Shinkai also found that TPH
may play a role in the negative symptoms in male patients with schizophrenia.5
In our study, −6526A/G showed significant differences between patients who had not attempted suicide (NSA) and HS (p
0.0329). The change of only one base pair (A→G) at −6526 strongly modifies the effect of this haplotype; TCAAA (p
0.00243) in −7180/−7065/−6526/218/779 seems to be a vulnerability haplotype , while TCGAA (p
0.0091) seems to be protective It suggests that the SNP −6526A/G is a potential suicide related site, with the A allele increasing the risk of suicide in patients, and it also explains the dose dependent effect of TPH1 A218 on the risk of suicidal behaviour shown in the meta‐analysis performed by Malafosse A.7
Patients with schizophrenia account for 92.1% of the NSA group, so we consider that the SNP −6526A/G may also be a locus for the aetiology of schizophrenia.
Our haplotype analysis suggests that the most common haplotype TCAAA, which was significantly more frequent in cases than in controls, might carry one or more predisposing variants. Interestingly, by comparison, the haplotype TCGAA, which was more frequent in controls than in cases, contained a variant that was likely to be protective against the disorder. Our case control study has independently replicated an association between TPH1 and suicidal behaviour. In our work, we observed the five marker haplotypes −7180G/T, −7065C/T, −6526A/G, 218A/C, and 779A/C to be significantly associated with psychiatric disorders in the Chinese population. The analysis of three marker haplotypes also show significance in every three adjacent marker that is in linkage disequilibrium (tables 5–8), which suggests that there is complicated linkage and crossover between these five markers. It is difficult to interpret these conflicting results because of lack of power, ethnic heterogeneity, and variations in the sampling strategies (in particular for controls) and in polymorphisms of the TPH
gene and others we studied. The relatively small sample size does not exclude the possibility of false positive results and the finding needs replication. Individual SNPs, which are not very informative, are more likely than haplotypes to give unstable frequencies among different populations in association studies of this complex disorder. The complexity of the phenotype of suicide may reflect multiple biological and social aetiological factors, and presents a worthwhile area for genetic studies. TPH
or a gene in its vicinity may influence the psychiatry of suicidal behaviour. This region contains loci for several important genes, including those for Beckwith‐Wiedemann syndrome and tyrosine hydroxylase.37
The potentially confusing effect of population stratification is also a factor. Both environmental and genetic factors, as well as their interactions, are likely to contribute to the risk of suicide and psychiatric disorders.
In conclusion, our data were most consistent with a risk haplotype TCAAA in TPH1 for suicidal behaviour and psychiatric disorders. The lack of statistical significance with the individual markers probably implies that only one SNP genotyped in this work, −6526A/G, is directly involved in causing the disease. Replication of these findings in more independent samples is also essential to clarify the aetiology of suicide. Functional variations remain to be identified and subsequently tested for association with suicide related behaviour.