Genetics of plasma dopamine beta-hydroxylase activity in schizophrenia

描述(申请人提供)：多巴胺β-羟基酶(DBH)将多巴胺(DA)转化为去甲肾上腺素(NE)，可在血浆中进行检测，其活性受基因控制的寡聚机制控制。虽然基于表型标记的连锁研究和分子关联研究表明，结构基因胸径是调节血浆胸径活性的一个主要数量性状基因座，但这一假说从未被分子连锁分析验证过。有证据表明，至少有一个额外的基因座参与调节血浆胸腺激素活性，但该基因座的身份尚不清楚。确定负责调节血浆DBH的基因座对于精神分裂症(SCZ)的遗传学研究很重要，因为有几条证据表明，血浆DBH活性的差异与SCZ的表型呈现的差异有关。此外，大量证据表明，多巴胺和去甲肾上腺素药物神经传递的改变影响与SCZ精神病理学相关的核心表型，如执行和工作记忆。因此，我们假设DBH是SCZ中的一个修饰基因，它与易感基因相互作用，改变疾病的症状和病程。本申请提出四个目标：(1)在一组可获得血浆样本的SCZ家系中进行血浆胸径活性的连锁分析；(2)对该连锁研究进行后续关联分析，以确定负责调节血浆胸径的基因座和特定变异；(3)在更大的SCZ家系集合中进行SCZ连锁分析，条件是已建立的胸径上的2个SNPs与血浆胸径活性密切相关；以及(4)在这些家系的先证者中进行关联分析，以检验DBH调节SNPs与症状和病程改变相关的假设。这项拟议的工作对公共卫生具有重要意义，因为SCZ是一种常见的疾病，通常会在人们进入成年期时致残，导致巨大的生产力成本，给医疗保健和刑事司法系统带来巨大负担，并给患者及其家人带来巨大的人类痛苦。确定SCZ中不同结果的预测因素将为制定有针对性的干预措施开辟新的途径，这些干预措施可以显著改善SCZ对个人和社会的影响。

DESCRIPTION (provided by applicant): Dopamine beta-hydroxylase (DbH) converts dopamine (DA) to norepinephrine (NE), and can be assayed in the plasma, where its activity is under genetic control by an oligogenic mechanism. While linkage studies based on phenotypic markers, and molecular association studies, suggest the structural gene DBH is a major quantitative trait locus regulating plasma DbH activity, this hypothesis has never been tested by molecular linkage analysis. There is evidence for at least one additional locus contributing to the regulation of plasma DbH activity, but the identity of this locus is unknown. Identifying the loci responsible for regulating plasma DbH is important for genetic research on schizophrenia (SCZ), because several lines of evidence suggest that differences in plasma DbH activity associate with differences in the phenotypic presentation of SCZ. In addition, abundant evidence suggests that alteration in DA- and NE-medicated neuro-transmission influence core phenotypes relevant to SCZ psychopathology, such as executive and working memory. We therefore hypothesize that DBH is a modifying gene in SCZ, that interacts with susceptibility loci to alter the symptoms and course of the illness. This application proposes 4 aims: (1) to conduct linkage analysis of plasma DbH activity in a set of SCZ pedigrees from which plasma samples are available; (2) to conduct follow-up association analysis of that linkage study to identify loci and specific variants responsible for regulating plasma DbH; (3) to conduct a linkage analysis of SCZ in a larger collection of SCZ families, conditional on genotypes at 2 SNPs at DBH already established to associate strongly with plasma DbH activity; and (4) to conduct association analyses in the probands of those families to test the hypothesis that DbH-regulating SNPs associate with altered symptomatic profiles and course of illness. The proposed work is significant for the public health because SCZ is a common disorder that usually disables people just as they enter adulthood, leading to huge costs in productivity, large burdens on healthcare and criminal-justice systems, and enormous human suffering by patients and their families. Identifying predictors of varying outcomes in SCZ would open new avenues for development of targeted interventions that could significantly ameliorate the impact of SCZ on individuals and society.