TY - JOUR
T1 - Identification of four variants in the tryptophan hydroxylase promoter and association to behavior
AU - Rotondo, A.
AU - Schuebel, K. E.
AU - Bergen, A. W.
AU - Aragon, R.
AU - Virkkunen, M.
AU - Linnoila, M.
AU - Goldman, D.
AU - Nielsen, D. A.
N1 - Funding Information:
We thank Longina Akhtar for her excellent technical assistance, Dr Chiara Mazzanti for her molecular genetic assistance, and Dr Raymond Peterson for his statistical genetic assistance. A Rotondo was in part supported by the IDEA Association (Institute for the Treatment and Prevention of Depression and Anxiety), via Statuto 8, 20121 Milan, Italy, and by the Association Fredom From Fear, 308 Seaview Avenue, Staten Island, New York, NY 10303, USA.
PY - 1999
Y1 - 1999
N2 - One of the most replicated findings in biological psychiatry is the observation of lower 5-hydroxyindoleacetic acid concentrations, the major metabolite of serotonin, in the brain and cerebrospinal fluid of subjects with impulsive aggression. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin, however functional variants have not been reported from the coding sequence of this gene. Therefore, we screened the human TPH promoter (TPH-P) for genetic variants which could modulate TPH gene transcription. The TPH-P (2093 nucleotides) was screened for sequence variation by SSCP analysis of 260 individuals from Finnish, Italian, American Caucasian, and American Indian populations. Four common polymorphisms were idenfified: -7180T>G, -7065C>T, -6526A>G, and -5806G>T (designated as nucleotides upstream of the translation start site). In the Finns, the four polymorphisms had a minor allele frequency of 0.40 and in this population linkage disequilibrium between the four loci was complete. In the other populations the minor allele frequencies ranged from 0.40 to 0.45. TPH -6526A>G genotype was determined in 167 unrelated Finnish offenders and 153 controls previously studied for the TPH IVS7+779C>A polymorphism. A significant association was observed between -6526A > G and suicidality in the offenders. TPH -6526A>G and the previously reported intron seven polymorphism, TPH IVS7+779C>A, exhibited a normalised linkage disequilibrium of 0.89 in Finns. Normalized linkage disequilibrium was reduced in other populations, being 0.49 and 0.21 in Italians and American Indians, respectively. In conclusion, four TPH-P variants were identified which can be used for haplotype-based analysis to localize functional TPH alleles influencing behavior.
AB - One of the most replicated findings in biological psychiatry is the observation of lower 5-hydroxyindoleacetic acid concentrations, the major metabolite of serotonin, in the brain and cerebrospinal fluid of subjects with impulsive aggression. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin, however functional variants have not been reported from the coding sequence of this gene. Therefore, we screened the human TPH promoter (TPH-P) for genetic variants which could modulate TPH gene transcription. The TPH-P (2093 nucleotides) was screened for sequence variation by SSCP analysis of 260 individuals from Finnish, Italian, American Caucasian, and American Indian populations. Four common polymorphisms were idenfified: -7180T>G, -7065C>T, -6526A>G, and -5806G>T (designated as nucleotides upstream of the translation start site). In the Finns, the four polymorphisms had a minor allele frequency of 0.40 and in this population linkage disequilibrium between the four loci was complete. In the other populations the minor allele frequencies ranged from 0.40 to 0.45. TPH -6526A>G genotype was determined in 167 unrelated Finnish offenders and 153 controls previously studied for the TPH IVS7+779C>A polymorphism. A significant association was observed between -6526A > G and suicidality in the offenders. TPH -6526A>G and the previously reported intron seven polymorphism, TPH IVS7+779C>A, exhibited a normalised linkage disequilibrium of 0.89 in Finns. Normalized linkage disequilibrium was reduced in other populations, being 0.49 and 0.21 in Italians and American Indians, respectively. In conclusion, four TPH-P variants were identified which can be used for haplotype-based analysis to localize functional TPH alleles influencing behavior.
KW - Aggression
KW - Genetic polymorphisms
KW - Promoter
KW - Serotonin
KW - Suicidality
KW - Tryptophan hydroxylase
KW - Variant
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U2 - 10.1038/sj.mp.4000578
DO - 10.1038/sj.mp.4000578
M3 - Article
C2 - 10483053
AN - SCOPUS:0032846705
SN - 1359-4184
VL - 4
SP - 360
EP - 368
JO - Molecular psychiatry
JF - Molecular psychiatry
IS - 4
ER -