Harvey Mario, Gagné Bernard, Labbé Michel, Barden Nicholas
Department of Neuroscience, CHUL Research Centre and Laval University, Sainte-Foy, Quebec, Canada.
Psychiatr Genet. 2007 Feb;17(1):17-22. doi: 10.1097/YPG.0b013e3280111877.
Tryptophan hydroxylase is the rate-limiting enzyme in the serotonin biosynthetic pathway and plays an important role in the regulation of serotonin levels. Recently, a brain-specific isoform, tryptophan hydroxylase 2 or n-tryptophan hydroxylase, has been discovered. Some studies reported genetic and functional associations between this isoform and bipolar disorder and/or major depressive disorder. The aim of this study was to investigate further association of genetic variants in French Canadian samples with bipolar disorders.
Genetic variants in the tryptophan hydroxylase 2 gene were genotyped in a case-control sample consisting of 225 affected individuals (191 bipolar I and 34 bipolar II) and 221 controls and in a collection of extended pedigrees and trios from the same population 357 nuclear families (201 bipolar I, 64 bipolar II, 79 recurrent major depressive disorder).
We determined linkage disequilibrium structure in our isolated population and analyzed six tagged single nucleotide polymorphisms in the case-control sample. Whereas no single, single nucleotide polymorphism gave any significant result, a three single nucleotide polymorphism haplotype gave a global P=0.01. Family-based association showed significant association (P=0.004) of one polymorphism (rs4290270) with the major allele overtransmitted to affected offspring.
Case-control and family-based association studies further support the presence of a susceptibility locus for bipolar disorder in tryptophan hydroxylase 2 by showing statistically significant associations with both, single nucleotide polymorphism alone and haplotype of single nucleotide polymorphism markers.
色氨酸羟化酶是5-羟色胺生物合成途径中的限速酶，在5-羟色胺水平的调节中起重要作用。最近，已发现一种脑特异性同工型，即色氨酸羟化酶2或n-色氨酸羟化酶。一些研究报道了这种同工型与双相情感障碍和/或重度抑郁症之间的遗传和功能关联。本研究的目的是进一步调查法裔加拿大样本中基因变异与双相情感障碍的关联。
在一个病例对照样本（由225名受影响个体组成，其中191例为双相I型，34例为双相II型，以及221名对照）和来自同一人群的357个核心家庭（201例双相I型，64例双相II型，79例复发性重度抑郁症）的扩展家系和三联体中，对色氨酸羟化酶2基因中的基因变异进行基因分型。
我们确定了我们隔离人群中的连锁不平衡结构，并在病例对照样本中分析了六个标签单核苷酸多态性。虽然没有单个单核苷酸多态性给出任何显著结果，但一个三个单核苷酸多态性单倍型给出了全局P=0.01。基于家系的关联显示，一个多态性（rs4290270）与过度传递给受影响后代的主要等位基因有显著关联（P=0.004）。
病例对照和基于家系的关联研究通过显示与单核苷酸多态性单独以及单核苷酸多态性标记的单倍型均有统计学显著关联，进一步支持了色氨酸羟化酶2中存在双相情感障碍的易感基因座。
