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Ann Van Den Bogaert, PhD; Kristel Sleegers, MD, PhD; Sonia De Zutter; Lien Heyrman; Karl-Fredrik Norrback, MD, PhD; Rolf Adolfsson, MD, PhD; Christine Van Broeckhoven, PhD, DSc; Jurgen Del-Favero, Ir, PhD

Arch Gen Psychiatry. 2006;63:1103-1110.

Context  Tryptophan hydroxylase is the rate-limiting enzyme in the serotonin (5-HT) biosynthetic pathway responsible for the regulation of serotonin levels. Tryptophan hydroxylase 2 (TPH2) was found to be solely expressed in the brain and therefore considered an important susceptibility gene in psychiatric disorders.

Objective  To determine the role of the brain-specific TPH2 gene in unipolar (UP) disorder and bipolar (BP) disorder in a northern Swedish, isolated population.

Design  HapMap-based haplotype-tagging single nucleotide polymorphism (htSNP) patient-control association study.

Setting  A northern Swedish, isolated population.

Participants  One hundred thirty-five unrelated patients with UP disorder, 182 unrelated patients with BP disorder, and 364 unrelated control individuals.

Results  Significant allelic association was identified in our UP disorder association sample for an htSNP located in the 5' promoter region (rs11178997; P = .001). Haplotype analysis supported this significant result by the presence of a protective factor on hapblock 2 (P_specific = .002). In the BP disorder association sample, single-marker association identified a significant htSNP in the upstream regulatory region (rs4131348; P = .004). Moreover, haplotype analysis in the BP disorder sample showed that the same htSNPs from hapblock 2 associated with UP disorder were also significantly associated with BP disorder (P_specific = .002).

Conclusions  Haplotype-based analysis of TPH2 in patients with UP and BP disorder and controls from northern Swedish descent provides preliminary evidence for protective association in both disorders and thus supports a central role for TPH2 in the pathogenesis of affective disorders.

Author Affiliations: Applied Molecular Genomics Group (Drs Van Den Bogaert and Del-Favero, Ms De Zutter, and Mr Heyrman) and Neurodegenerative Brain Disease Group, Department of Molecular Genetics (Drs Sleegers and Van Broeckhoven), Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium; Department of Clinical Sciences, Division of Psychiatry, University of Umeå, Umeå, Sweden (Drs Norrback and Adolfsson).

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