Tryptophan hydroxylase (TPH), being the rate-limiting enzyme in the biosynthesis of serotonin plays a major role as candidate gene in several psychiatric disorders. Recently, a second TPH isoform (TPH2) was identified in mice, which was exclusively present in the brain. In a previous post-mortem study of our own group, we could demonstrate that TPH2 is also expressed in the human brain, but not in peripheral tissues. This is the first report of an association study between polymorphisms in the TPH2 gene and major depression (MD). We performed singlenucleotide polymorphism (SNP), haplotype and linkage disequlibrium studies on 300 depressed patients and 265 healthy controls with 10 SNPs in the TPH2 gene. Significant association was detected between one SNP (P ¼ 0.0012, global P ¼ 0.0051) and MD. Haplotype analysis produced additional support for association (Po0.0001, global P ¼ 0.0001). Our findings provide evidence for an involvement of genetic variants of the TPH2 gene in the pathogenesis of MD and might be a hint on the repeatedly discussed duality of the serotonergic system. These results may open up new research strategies for the analysis of the observed disturbances in the serotonergic system in patients suffering from several other psychiatric disorders.

The influence of genetic factors in schizophrenia has been convincingly demonstrated by family, twin and adoption studies, but the mode of transmission remains uncertain. The reported pattern of recurrence risks suggests a set of interacting loci. Based on prior evidence for linkage on chromosome 6p (K. Kendler, pers. comm.), we have scanned the short arm of chromosome 6 in 54 families for loci predisposing to schizophrenia, using 25 microsatellite markers spanning 60 centiMorgans (cM). Allele sharing identity by descent was examined in affected sib-pairs from these families, followed by multipoint sib-pair linkage analysis. Positive lod scores were obtained over a wide region (D6S470 to D6S271), with a maximum lod score of 2.2 occurring near D6S274, located in 6p22. However, we obtained a lod score of -2 at D6S296, the locus found by others to provide the greatest linkage evidence. At D6S274, we report a positive lod score as do Straub et al. (individually non-significant). A combined total lod of 3.6-4.0 suggests the possibility of a susceptibility locus in this region. However, methodological differences between our studies makes a firm conclusion difficult.

The results of the present study suggest that the s-allele of the 5HTTLPR and a positive family history of depression are additive risk factors for the development of depression during TD.

Objective. To analyze the genotypes of the promoter region of the serotonin transporter gene (5-HTT) in patients with fibromyalgia (FM).Methods. Genomic DNA from 62 patients meeting the American College of Rheumatology 1990 criteria for FM and 110 healthy controls was analyzed by polymerase chain reaction. Additionally, the psychopathologic state of 52 of the FM patients was evaluated using the Beck Depression Inventory (BDI) and the Symptom Checklist-90-Revised (SCL-90-R).Results. The 5-HTTLPR genotypes in FM patients versus controls were distributed as follows: L/L 27% versus 34%, L/S 42% versus 50%, and S/S 31% versus 16%. FM patients with the S/S genotype had higher mean scores on the BDI and the SCL-90-R compared with those in the L/L and L/S groups.Conclusion. A higher frequency of the S/S genotype of 5-HTT was found in FM patients compared with healthy controls. The S/S subgroup exhibited higher mean levels of depression and psychological distress. These results support the notion of altered serotonin metabolism in at least a subgroup of patients with FM.Fibromyalgia (FM) is a syndrome of unknown etiology characterized by chronic widespread pain, increased tenderness on palpation, and additional symptoms such as disturbed sleep, stiffness, fatigue, and psychological distress (1). The pathophysiologic mechanisms underlying FM have been hypothetically linked to disturbances in serotonin (5-HT) metabolism and transmission (2). This hypothesis is based on several recent findings. Studies have shown that levels of tryptophan (the precursor of serotonin) and other amino acids are decreased in sera of FM patients (3), that FM patients have an abnormal serum tryptophan transport ratio (4), and that 5-HT serum levels in FM patients are lower compared with controls (2,5). Similar abnormalities regarding 5-HT metabolism have been found in the cerebrospinal fluid of FM patients (6,7).Uptake of 5-HT from the synaptic cleft by the serotonin transporter (5-HTT) into the presynaptic neuron plays a critical role in the termination of serotonergic transmission. Decreased imipramine binding, labeling of the allosteric site of the 5-HTT, and decreased 5-HT re-uptake in platelets and brain tissue of patients with affective disorders and of suicide victims have been consistently reported (8-10). However, in FM there are conflicting results regarding imipramine binding in platelets (11,12).Human 5-HTT is encoded by a single gene (SLC6A4) on chromosome 17q12. Recently, a polymorphism in the transcriptional region, composed of a 44-basepair insertion ("long allele" [L]) or deletion ("short allele" [S]), has been described (13). In vitro studies of the functional effects of this polymorphism showed that the long variant is associated with a 3-fold increase in transcriptional activity. It was also found that levels of serotonin transporter messenger RNA (mRNA) and serotonin uptake capacity were reduced in lymphoblastoid cell lines derived from individuals with 1 or 2 copies of the short allele (13). Therefore, by regulating the mag...

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