Molecular Genetics of Bipolar Disorder

描述（由申请人提供）：该指导研究科学家职业发展奖（K01）提案是一个为期四年的计划，使候选人能够发展成为精神病学遗传学领域的独立研究者。该提案为他在生物信息学，基因阵列技术和基于snp的连锁不平衡（LD）研究方面的技能提供了广泛的发展。这些短期的职业目标将通过正式的课程学习，在合作环境中广泛的指导，以及一个研究计划的实施来完成，这个研究计划将形成一个旨在调查双相情感障碍分子遗传学的更大研究机构的基础。指导将由精神科神经生物学主任Christopher A. Ross博士和George Browne遗传学实验室主任Melvin G. Mclnnis博士提供。精神科主任J. Raymond DePaulo博士将继续在临床实践和精神遗传分析方面提供专家咨询。Drs。Aravinda Chakravarti, Terri Beaty， Jonathan Pevsner和Forrest Spencer将提供生物信息学，LD和微阵列分析方面的专家咨询。NIMH情绪和焦虑障碍遗传基础主任Francis McMahon博士将为SNP基因分型技术提供设施和帮助。教学训练将由拟议的研究项目补充，该项目旨在测试基因变异是双相情感障碍易感性的基础这一假设。这一假设得到了双胞胎、收养和家庭研究以及最近与人类基因组中许多区域相关的报告的支持。本项目将利用在DePaulo博士指导下编制的有价值的双相情感障碍家族数据集，并显示与18q21-22区域有很强的联系。具体目标是1)。开发针对18q21-22区域的定制基因阵列，用于BPD中表达改变和/或剪接变异基因的表达谱分析和鉴定；2）. 利用微阵列分析鉴定BPD患者死后脑和新鲜血液样本中表达改变的基因，并利用更准确的RT-PCR分析验证阵列实验中的重要发现；3）. 目的鉴定双相谱系中18q21-22的snp并进行基因分型，并利用LD分析检测与BPD相关的等位基因或单倍型。

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.