SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression

• Published in: Molecular psychiatry Vol. 9; no. 11; pp. 1030 - 1036
• Main Authors: ZILL, P, BAGHAI, T. C, ZWANZGER, P, SCHÜLE, C, ESER, D, RUPPRECHT, R, MÖLLER, H.-J, BONDY, B, ACKENHEIL, M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.11.2004
• Subjects: Adult; Adult and adolescent clinical studies; Biological and medical sciences; Brain - enzymology; Chromosomes, Human, Pair 12 - genetics; Depression; Depressive Disorder, Major - enzymology; Depressive Disorder, Major - genetics; Female; Gene Frequency; Gene polymorphism; Genetic diversity; Genetic Predisposition to Disease; Haplotypes; Haplotypes - genetics; Humans; Isoenzymes - genetics; Linkage Disequilibrium - genetics; Lod Score; Male; Medical sciences; Mental depression; Mental disorders; Middle Aged; Mood disorders; Polymorphism, Single Nucleotide - genetics; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Serotonin; Serotonin - genetics; Single-nucleotide polymorphism; Tryptophan; Tryptophan hydroxylase; Tryptophan Hydroxylase - genetics; Mood disorder; Human; Serotonin; Enzyme; Depression; Biosynthesis; Linkage equilibrium; Gene expression; Tryptophan 5-monooxygenase; Neurotransmitter; Candidate gene; Oxidoreductases; Haplotype; Polymorphism
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/sj.mp.4001525

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 single-nucleotide 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=0.0012, global P=0.0051) and MD. Haplotype analysis produced additional support for association (P<0.0001, global P=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.