Haplotype analysis reveals tryptophan hydroxylase (TPH) 1 gene variants associated with major depression.
BACKGROUND
Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin (5-HT) and might be related to the pathogenesis of major depression (MD). Two isoforms are known, TPH-1 and TPH-2. Tryptophan hydroxylase-1 association with MD is still debated.


METHODS
A single nucleotide polymorphism (SNP) screening strategy was used to define TPH-1 haplotypes spanning over 23 kilobase (kb) of the 29 kb gene length. Genotyping was performed in 228 MD patients and 253 healthy control subjects.


RESULTS
Six SNPs were found at linkage disequilibrium in both patients and control subjects, suggesting a haplotype block structure. Single marker association analyses showed only one SNP significantly associated with MD. Several haplotypes were associated with MD. When all six locus haplotypes were divided into two groups, above or below a 5% threshold, the compound haplotype group below a 5% frequency resulted as associated with the disease (31.6% vs. 18.0% in control subjects, p < 10(-5)). A "sliding window" analysis attributed the strongest disease association to a haplotype configuration localized between introns 7 and 8 (p < 10(-5)).


CONCLUSIONS
Haplotype analysis indicates that TPH-1 associates with MD. The most common TPH-1 variants appear to carry no risk, while some of the less frequent variants might contribute to genetic predisposition to MD.
Gizatullin
Rinat
R
Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institute and Hospital, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
Zaboli
Ghazal
G
Jönsson
Erik G
EG
Asberg
Marie
M
Leopardi
Rosario
R
D015415:Biomarkers; D003865:Major Depressive Disorder / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014365:Tryptophan Hydroxylase / Q000235:genetics*
D015415:Biomarkers; C497467:TPH1 protein, human; D014365:Tryptophan Hydroxylase