Genetic architecture of the human tryptophan hydroxylase 2 Gene: existence of neural isoforms and relevance for major depression

• Published in: Molecular psychiatry Vol. 13; no. 8; pp. 813 - 820
• Main Authors: Haghighi, F, Bach-Mizrachi, H, Huang, Y Y, Arango, V, Shi, S, Dwork, A J, Rosoklija, G, Sheng, H T, Morozova, I, Ju, J, Russo, J J, Mann, J J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2008; Nature Publishing Group
• Subjects: Adenine; Adult and adolescent clinical studies; Amygdala; Autopsies; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Brain - enzymology; Brain stem; Chromosome Mapping; Depression; Depressive Disorder, Major - enzymology; Depressive Disorder, Major - genetics; European Continental Ancestry Group; Genetic aspects; Guanine; Humans; Hydroxylases; Isoenzymes - genetics; Isoforms; Major depressive disorder; Medical sciences; Medicine; Medicine & Public Health; Mental depression; Mental disorders; Mood disorders; Neurons - enzymology; Neurosciences; Neurotransmission; original-article; Pharmacotherapy; Polymorphism, Single Nucleotide; Prefrontal cortex; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology; Psychopathology. Psychiatry; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; Serotonin; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Suicidal behavior; Suicide; Suicides & suicide attempts; Tryptophan; Tryptophan hydroxylase; Tryptophan Hydroxylase - genetics; United States; New York; United States > US; genetic association; TPH2; tryptophan hydroxylase 2; Haplotype; major depression; suicide; Mood disorder; Human; Molecular form; Architecture; Enzyme; Depression; Suicide; Genetic determinism; Gene; Tryptophan 5-monooxygenase; Genetics; Oxidoreductases
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/sj.mp.4002127

Impaired brain serotonin neurotransmission is a potential component of the diathesis of major depression. Tryptophan hydroxylase-2 (TPH2), is the rate limiting biosynthetic isoenzyme for serotonin that is preferentially expressed in the brain and a cause of impaired serotonin transmission. Here, we identify a novel TPH2 short isoform with truncated catalytic domain expressed in human brainstem, prefrontal cortex, hippocampus and amygdala. An exploratory study of 166 Caucasian subjects revealed association with major depression or suicide of a novel single nucleotide polymorphism (SNP) g.22879A>G located in exon 6 of this short isoform. This SNP and additional SNPs were discovered through a systematic characterization of the genetic architecture of the TPH2 gene for further genetic and functional investigations of its relationship to major depression and other psychopathology.