BACKGROUND:Despite proven heritability, little is known about the genetic architecture of mood disorders. Although a number of family and case-control studies have examined the genetics of mood disorders, none have carried out joint linkage-association studies and sought to validate the results with gene expression analyses in an independent cohort. METHODS:We present findings from a large candidate gene study that combines linkage and association analyses using families and singletons, providing a systematic candidate gene investigation of mood disorder. For this study, 876 individuals were recruited, including 83 families with 313 individuals and 563 singletons. This large-scale candidate gene analysis included 130 candidate genes implicated in addictive and other psychiatric disorders. These data showed significant genetic associations for 28 of these candidate genes, although none remained significant after correction for multiple testing. To evaluate the functional significance of these 28 candidate genes in mood disorders, we examined the transcriptional profiles of these genes within the dorsolateral prefrontal cortex and anterior cingulate for 21 cases with mood disorders and 25 nonpsychiatric controls, and carried out a pathway analysis to identify points of high connectivity suggestive of particular molecular pathways that may be dysregulated. RESULTS:Two primary gene candidates were supported by the linkage-association, gene expression profiling, and network analysis: neurotrophic tyrosine kinase receptor, type 2 (NTRK2), and the opioid receptor, κ1 (OPRK1). CONCLUSION:This study supports a role for NTRK2 and OPRK1 signaling in the pathophysiology of mood disorder. The unique approach incorporating evidence from multiple experimental and computational modalities enhances confidence in these findings.

译文

背景:尽管遗传力得到证实,但对情绪障碍的遗传结构知之甚少。尽管许多家庭和病例对照研究已经检查了情绪障碍的遗传学,但没有一项进行联合连锁关联研究,并试图通过独立队列中的基因表达分析来验证结果。
方法:我们提出了一项来自大型候选基因研究的发现,该研究结合了使用家族和单身人士的连锁和关联分析,为情绪障碍提供了系统的候选基因研究。这项研究招募了876个人,包括83个家庭,其中313个人和563单身人士。这项大规模的候选基因分析包括130项与成瘾性和其他精神疾病有关的候选基因。这些数据显示了其中28个候选基因的显着遗传关联,尽管在进行多次测试校正后,这些关联都没有显着性。为了评估这28个候选基因在情绪障碍中的功能意义,我们检查了21例情绪障碍和25个非精神病患者的背外侧前额叶皮层和前扣带回中这些基因的转录谱,并进行了通路分析以识别点高连通性表明可能失调的特定分子途径。
结果:两个主要的候选基因得到了连锁关联,基因表达谱和网络分析的支持:神经营养型酪氨酸激酶受体2型(NTRK2)和阿片受体κ1(OPRK1)。
结论:本研究支持NTRK2和OPRK1信号传导在情绪障碍的病理生理中的作用。独特的方法结合了来自多种实验和计算方式的证据,增强了对这些发现的信心。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录