Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany.
Transl Psychiatry. 2012 Apr 17;2(4):e103. doi: 10.1038/tp.2012.30.
Serotonin type 3 receptors (5-HT(3)) are involved in learning, cognition and emotion, and have been implicated in various psychiatric phenotypes. However, their contribution to the pathomechanism of these disorders remains elusive. Three single nucleotide polymorphisms (SNPs) in the HTR3A and HTR3B genes (rs1062613, rs1176744 and rs3831455) have been associated with bipolar affective disorder (BPAD) in pilot studies, and all of them are of functional relevance. We performed a European multicenter study to confirm previous results and provide further evidence for the relevance of these SNPs to the etiology of neuropsychiatric disorders. This involved analysis of the distribution of the three SNPs among 1804 BPAD cases and 2407 healthy controls. A meta-analysis revealed a pooled odds ratio of 0.881 (P = 0.009, 95% confidence intervals = 0.802-0.968) for the non-synonymous functional SNP HTR3B p.Y129S (rs1176744), thereby confirming previous findings. In line with this, the three genome-wide association study samples BOMA (Bonn-Mannheim)-BPAD, WTCCC (Wellcome Trust Case Control Consortium)-BPAD and GAIN (Genetic Association Information Network)-BPAD, including >3500 patients and 5200 controls in total, showed an overrepresentation of the p.Y129 in patients. Remarkably, the meta-analysis revealed a P-value of 0.048 (OR = 0.934, fixed effect model). We also performed expression analyses to gain further insights into the distribution of HTR3A and HTR3B mRNA in the human brain. HTR3A and HTR3B were detected in all investigated brain tissues with the exception of the cerebellum, and large differences in the A:B subunit ratio were observed. Interestingly, expression of the B subunit was most prominent in the brain stem, amygdalae and frontal cortex, regions of relevance to psychiatric disorders. In conclusion, the present study provides further evidence for the presence of impaired 5-HT(3) receptor function in BPAD.
5-羟色胺 3 型受体（5-HT(3)）参与学习、认知和情绪，与各种精神疾病表型有关。然而，它们在这些疾病的发病机制中的作用仍不清楚。HTR3A 和 HTR3B 基因中的三个单核苷酸多态性（SNP）（rs1062613、rs1176744 和 rs3831455）在初步研究中与双相情感障碍（BPAD）有关，并且它们都具有功能相关性。我们进行了一项欧洲多中心研究，以确认先前的结果，并为这些 SNP 与神经精神疾病病因学的相关性提供进一步证据。这包括分析三个 SNP 在 1804 例 BPAD 病例和 2407 例健康对照中的分布。荟萃分析显示，非同义功能 SNP HTR3B p.Y129S（rs1176744）的合并优势比为 0.881（P = 0.009，95%置信区间为 0.802-0.968），从而证实了先前的发现。与此一致的是，三个全基因组关联研究样本 BOMA（波恩-曼海姆）-BPAD、WTCCC（惠康信托病例对照联合会）-BPAD 和 GAIN（遗传关联信息网络）-BPAD，总共包括 >3500 例患者和 5200 例对照，患者中 p.Y129 的代表性过高。值得注意的是，荟萃分析显示 P 值为 0.048（OR = 0.934，固定效应模型）。我们还进行了表达分析，以进一步了解 HTR3A 和 HTR3B mRNA 在人脑中的分布。除了小脑外，在所有研究的脑组织中均检测到 HTR3A 和 HTR3B，并且观察到 A:B 亚基比率的巨大差异。有趣的是，B 亚基的表达在脑干、杏仁核和额叶皮质最为明显，这些区域与精神疾病有关。总之，本研究为 BPAD 中存在 5-HT(3) 受体功能受损提供了进一步证据。
