Tryptophan 2,3-Dioxygenase--Candidate Gene For Disorders

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Genetic variations in the enzymes involved in serotonin metabolism may contribute to a wide range of neuropsychiatric diseases, from eating disorders, obsessive-compulsive disorder and alcoholism to autism. Tryptophan, obtained only from the diet in humans, is converted to serotonin by tryptophan hydroxylase, or to kynurenine by tryptophan 2,3-dioxygenase (TDO2). Both enzymes are rate limiting in their respective pathways. The purpose of this study is to screen the TD02 gene for polymorphisms, assess functionality, and search for disease associations. The original research method was single-strand conformational polymorphism (SSCP) analysis. Most of the coding region (11 of the 12 exons), the intronic sequence and the promoter region was successfully amplified and screened across populations with alcoholism, impulsivity, anorexia or bulimia nervosa, obsessive-compulsive disorder, autism, major depression and suicidality, and subjects enrolled in a tryptophan depletion study. No associations were found for polymorphisms in introns 5, 6 or 11 nor for a variant in exon 7 (A to C, 749 Asn to His). In the SSCP screening of the promoter region no polymorphisms were found in the regions of two TATA boxes. Two variants have been detected in the putative promoter glucocorticoid response elements. The promoter, coding region and introns have been screened by Denaturing High Performance Liquid Chromatography (DHPLC) to look for further polymorphisms and confirm those already found. 5? exonuclease assays have been developed for 14 single nucleotide polymorphisms (SNPs) spanning the coding region of the gene and for 2 SNPs and one GTT insertion in the promoter region. These 17 polymorphisms have now been genotyped in 4 populations; 673 Finnish Caucasians, 220 US Caucasians, 337 Plains American Indians and 280 African Americans. Haplotype blocks have been identified and haplotype-based association studies for alcoholism are underway.