Molecular Genetics of Bipolar Disorder

描述(申请人提供)：这是一项为期四年的计划，旨在使候选人能够发展成为精神遗传学领域的独立研究人员。这项建议为他在生物信息学、基因阵列技术和基于SNP的连锁不平衡(LD)研究方面提供了广泛的技能发展。这些短期的职业目标将通过正式的课程工作、在合作环境中的广泛指导以及研究计划的实施来实现，该研究计划将构成旨在调查双相情感障碍的分子遗传学的更大主体研究的基础。导师将由精神病学系神经生物学部门主任克里斯托弗·A·罗斯博士和乔治·布朗遗传学实验室主任梅尔文·G·麦克尼斯博士提供。精神科主任J.Raymond DePaulo，Jr.博士将继续提供临床实践和精神基因分析方面的专家咨询。Aravinda Chakravarti博士、Terri Beaty博士、Jonathan Pevsner博士和Forrest Spencer博士将提供生物信息学、LD和微阵列分析方面的专家咨询。情绪和焦虑症遗传基础(NIMH)首席弗朗西斯·麦克马洪博士将提供SNP基因分型技术方面的设施和帮助。教学培训将得到拟议的研究项目的补充，该项目旨在测试基因变异导致双相情感障碍易感性的假设。这一假说已经通过双胞胎、收养和家庭研究以及最近关于与人类基因组中的一些区域相关联的报告得到了支持。这个项目将利用在DePaulo博士的指导下汇编的有价值的双相情感障碍家族数据集，并显示出与18q21-22区域的强大联系。具体目标有：1)。开发针对18q21-22区域的定制基因阵列，用于表达谱分析和鉴定BPD中表达和/或剪接变异的基因；利用基因芯片技术鉴定BPD患者死后脑和新鲜血液中表达改变的基因，并利用更准确的RT-PCR分析来验证阵列实验中有意义的发现；目的：对双相情感障碍家系中18q21-22的SNPs进行鉴定和分型，并用LD分析检测等位基因或单倍型与BPD的相关性。

DESCRIPTION (provided by applicant): This mentored research scientist career development award (K01) proposal is a four-year plan to enable the candidate to develop into an independent investigator in the field of psychiatric genetics. This proposal provides for extensive development of his skills in bioinformatics, gene array technology, and SNP-based linkage disequilibrium (LD) studies. These short-term career goals will be accomplished through formal course work, extensive mentorship in a collaborative environment, and implementation of a research plan that will form the basis of a larger body of research aimed at investigating the molecular genetics of bipolar disorder. Mentorship will be provided by Dr. Christopher A. Ross, Director of the Division of Neurobiology in the Department of Psychiatry, and Dr. Melvin G. Mclnnis, Director of the George Browne Genetics Laboratory. Dr. J. Raymond DePaulo, Jr., Director of the Department of Psychiatry will continue to provide expert consultation in clinical practice and psychiatric genetic analysis. Drs. Aravinda Chakravarti, Terri Beaty, Jonathan Pevsner, and Forrest Spencer will provide expert consultation in bioinformatics, LD and microarray analysis. Dr. Francis McMahon, Chief, Genetic Basis of Mood and Anxiety Disorders, NIMH, will provide facilities and assistance in SNP genotyping technology. The didactic training will be complemented by the proposed research project, which is designed to test the hypothesis that gene variations underlie susceptibility to bipolar disorder. This hypothesis has been supported through twin, adoption, and family studies and by recent reports of linkage to a number of regions in the human genome. This project will take advantage of the valuable bipolar disorder family data set that has been compiled under the direction of Dr. DePaulo, and showed strong linkage to the region of 18q21-22. The specific aims are 1). To develop a custom gene array specific to the 18q21-22 region for expression profiling and identification of genes with altered expression and/or splicing variances in BPD; 2). To identify by use of microarray analysis the genes with altered expression in postmortem brain and fresh blood samples from patients with BPD, and to use the more accurate RT-PCR analysis to verify significant findings in array experiments; 3). To identify and genotype SNPs in 18q21-22 in bipolar pedigrees, and to test for allelic or haplotype associations with BPD using LD analysis.