SNPs in Neurotransmitter Systems & Personality Traits

描述(由申请人提供)：确定抑郁症等复杂疾病风险的潜在遗传变异是极其困难的。为了补充抑郁症的连锁和关联研究，我们提出了神经质的遗传关联研究。神经质的遗传学与抑郁症的遗传学有很大的重叠，但它构成了一个可以在总体样本中测量的数量性状。神经质是用心理测量学上健全的、有效的新移民人格问卷来衡量的。我们的样本包括大约500个家系中的大约1500名受试者，这些受试者是通过高血压先证者确诊的，但没有被选中，还有大约200名低血压对照组。超过一半的受试者也接受了neo-PI，所有人都献血进行了基因DMA分析。在前470名受试者中，我们发现了两个与神经质有关的基因变异，这两个基因变异被其他实验室复制，并在其他研究中发现与情感障碍有关。这些发现证实了我们的基本假设，即识别影响神经质得分的基因变异将与情感障碍相关。此外，已经对我们的样本进行了全基因组扫描，并将分析其与包括神经质在内的人格特征的联系。在这项试点拨款中，我们建议继续进行候选基因分析。候选基因将通过我们的初步数据、正在进行的微阵列分析、文献和连锁分析来了解。根据我们的初步数据，我们将从参与5-羟色胺系统的候选基因开始。这些候选基因中的SNP将是已知的功能(编码或启动子)变体，或选自HapMap。DNA分析将使用一种新型的多重(15-30个SNPs)基因分型系统进行，并将与商业基因分型方法进行比较，以优化和确定错误率。核心家庭结构允许开展以人口为基础和以家庭为基础的关联研究。一种基于方差成分模型的关联检验被称为QTDT，它能够解释家族相似性，是这类分析的理想工具。据报道，在关联研究中，单倍型分析比单标记分析提供更多的信息，我们将使用广义线性模型来估计单倍型效应。最后，我们将比较不同联想测试的结果，并对最有趣的信号进行跟踪。预计在这个有价值的样本中，R21将导致对神经质的更彻底的、全基因组的遗传学研究。

DESCRIPTION (provided by applicant): Identifying genetic variants underlying the risk for complex disorders such as depression is extremely difficult. To complement linkage and association studies of depression, we propose a genetic association study of Neuroticism. The genetics of Neuroticism overlaps significantly with that of depression, but it constitutes a quantitative trait that can be measured in a population sample. Neuroticism is measured with the psychometrically sound, validated NEO personality inventory. Our sample consists of about 1500 subjects in about 500 families ascertained through a hypertensive proband but unselected otherwise, and about 200 hypotensive controls. More than half of the subjects have also been administered the NEO-PI, and all have given blood for genetic DMA analysis. With the first 470 subjects, we found two genetic variants associated with Neuroticism, which were replicated by other laboratories and also found associated with affective disorder in other studies. These findings confirm our underlying hypothesis that identification of genetic variants affecting Neuroticism scores will be relevant for affective disorders. In addition, a whole genome scan has been performed on our sample and will be analyzed for linkage to personality traits, including Neuroticism. In this pilot grant, we propose to continue candidate gene analysis. Candidate genes will be informed by our preliminary data, ongoing microarray analyses, the literature, and linkage analyses. We will start with candidate genes involved in the serotonin system due to our preliminary data. SNPs in these candidate genes will be either known functional (coding or promoter) variants, or selected from the HAPMAP. DNA analysis will be performed with a novel, multiplex (15-30 SNPs) genotyping system and will be compared to commercial genotyping methods for optimization and error rate determination. The nuclear family structure allows both population-based and family-based association studies to be carried out. A variance component model-based association test called QTDT, which is able to account for familial resemblance, is an ideal tool for this type of analysis Haplotype analyses are reported to be more informative than single marker analysis in association studies, and we will use generalized linear models to estimate haplotype effects. At the end, we will compare the results obtained from different association tests, and follow up on the most interesting signals. It is anticipated that this R21 will lead to a more thorough, genome-wide genetic study of Neuroticism in this valuable sample.