Association of brain-specific tryptophan hydroxylase, TPH2, with unipolar and bipolar disorder in a Northern Swedish, isolated population.
BACKGROUND
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.


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


METHODS
A northern Swedish, isolated population.


METHODS
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.
Van Den Bogaert
Ann
A
Applied Molecular Genomics Group, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium.
Sleegers
Kristel
K
De Zutter
Sonia
S
Heyrman
Lien
L
Norrback
Karl-Fredrik
KF
Adolfsson
Rolf
R
Van Broeckhoven
Christine
C
Del-Favero
Jurgen
J
D000368:Aged; D001714:Bipolar Disorder / Q000201:enzymology* / Q000208:ethnology / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D003866:Depressive Disorder / Q000201:enzymology* / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012701:Serotonin / Q000096:biosynthesis / Q000235:genetics; D013548:Sweden / Q000208:ethnology; D014365:Tryptophan Hydroxylase / Q000235:genetics*; D044465:White People / Q000235:genetics*
D005819:Genetic Markers; D012701:Serotonin; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase