Serotonin-related genes in human brain

描述(申请人提供)：概述神经递质5-羟色胺(5-羟色胺；5-羟色胺)在大脑发育和成人大脑中起着至关重要的作用。5-羟色胺能活动的中断被认为是导致严重的精神和神经发育障碍的因素，包括自闭症、严重抑郁症、焦虑症和精神分裂症。然而，5-羟色胺能活动如何受到个体间遗传差异的影响，目前还知之甚少。我们假设，导致异常高或低水平基因表达的基因变异会改变大脑的发育，使某些人在儿童或成年时容易患上严重的疾病。这项研究的目的是确定在发育中和成年人脑中调节关键5-羟色胺相关基因表达的常见遗传变异(多态)。利用尸检组织样本，我们将以等位基因特异性的方式量化发育中和成人脑桥、海马和额叶皮质中15个5-羟色胺相关基因的mRNAs表达。量化每个大脑样本中两个等位基因产生的mRNA水平，可以在不进行样本之间比较的情况下检测到特定于等位基因的表达差异。这种新的方法大大提高了测量的准确性和重复性。根据我们以前的经验，我们预计在我们选择的3-4个基因中，有3-4个基因在发育中和/或成人大脑中表现出显著和频繁的等位基因表达失衡(AEI)。AEI是由位于相应基因内或附近的调节性多态引起的。由于表达依赖于上下文，因此AEI的程度可能在不同的大脑区域和/或在发育中的大脑和成人大脑之间存在差异。该项目的主要目标之一是确定某些基因的AEI是否只发生在发育中的大脑中，就像已经提出的针对5-羟色胺转运体(SERT)的建议一样。对于显示AEI的基因，我们将在基因附近搜索杂合性与AEI相关的单核苷酸多态(SNPs)。高度相关的SNPs将被进一步研究，以确定它们是否在mRNA表达中发挥直接作用。我们将首先关注色氨酸羟化酶2(TPH2)的AEI机制，此前我们已经发现了几个高度相关的SNPs。TPH2和其他5-羟色胺相关基因的有效调节多态将成为诊断和分析主要精神和神经发育障碍的有价值的生物标记物。-相关性这项研究的目标是确定与5-羟色胺相关的基因中常见的调节变种，5-羟色胺是一种在发育中和成人大脑中发挥重要作用的神经递质。我们假设，显著改变关键5-羟色胺相关基因表达的基因变异会导致精神和神经发育障碍，包括自闭症、严重抑郁症、焦虑症和精神分裂症。识别调节关键的5-羟色胺相关基因的基因变异将是朝着开发诊断、治疗以及可能预防这些疾病的新方法迈出的重要一步。

DESCRIPTION (provided by applicant): Summary The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) plays a crucial role in developing and adult brain. Disruption of serotonergic activity has been proposed to contribute to major mental and neurodevelopmental disorders, including autism, major depression, anxiety disorders and schizophrenia. How serotoninergic activity is affected by genetic differences among individuals, however, is poorly understood. We hypothesize that genetic variants causing exceptionally high- or low-levels of gene expression alter the development of the brain in ways that predispose certain individuals to develop serious disorders as children or adults. The goal of this study is to identify common genetic variants (polymorphisms) that regulate the expression of key serotonin-related genes in developing and adult human brain. Using autopsy tissue samples, we will quantify the expression of mRNAs for 15 serotonin-related genes in developing and adult pons, hippocampus and frontal cortex in an allele-specific manner. Quantifying levels of mRNA produced from two alleles within each brain sample allows allele-specific differences in expression to be detected without making comparisons between samples. This novel approach greatly increases the accuracy and reproducibility of the measurements. Based upon our previous experience, we expect 3-4 of our selected genes to show significant and frequent allelic expression imbalance (AEI) in developing and/or adult brain. AEI is caused by regulatory polymorphisms located within or near the corresponding gene. Since expression is context-dependent, it is possible that the extent of AEI differs between brain regions and/or between developing and adult brain. One of the major objectives of this project is to determine whether AEI for certain genes occurs only in the developing brain, as has been proposed for the serotonin transporter (SERT). For genes that show AEI, we will search the neighborhood of the gene for single nucleotide polymorphisms (SNPs) for which heterozygosity correlates with AEI. Highly correlated SNPs will be further studied to determine whether they play a direct role in mRNA expression. We will first focus on AEI mechanisms for tryptophan hydroxylase 2 (TPH2) for which we have previously identified several highly correlated SNPs. Validated regulatory polymorphisms in TPH2 and other serotonin-related genes will be valuable biomarkers for diagnosing and analyzing major mental and neurodevelopmental disorders. -Relevance The goal of this study is to identify common regulatory variants in genes related to serotonin, a neurotransmitter that plays important roles in the developing and adult brain. We hypothesize that genetic variants that significantly alter the expression of key serotonin-related genes contribute to mental and neurodevelopmental disorders, including autism, major depression, anxiety disorders and schizophrenia. Identifying genetic variants that regulate key serotonin-related genes will be a significant step toward developing new methods for the diagnosis, treatment and, possibly, prevention of these disorders.