Molecular Genetics of Bipolar Disorder

该指导研究科学家职业发展奖（K 01）提案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调查员。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工作，在合作环境中广泛的指导，以及研究计划的实施来实现，该计划将形成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。将由Christopher A博士提供指导。精神病学系神经生物学部主任罗斯博士和梅尔文·G。麦克林尼斯，乔治布朗遗传学实验室主任。小J·雷蒙德·德保罗博士精神科主任将继续提供临床实践和精神病遗传分析方面的专家咨询。Aravinda Chakravarti，Terri Beaty，Jonathan Pevsner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。弗朗西斯麦克马洪博士，首席，情绪和焦虑障碍的遗传基础，NIMH，将提供设施和SNP基因分型技术的援助。教学培训将得到拟议研究项目的补充，该项目旨在检验基因变异是双相情感障碍易感性的基础这一假设。这一假说得到了双胞胎、收养和家庭研究的支持，最近的报告也证实了这一假说与人类基因组中的一些区域有关。该项目将利用在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18 q21 -22区域的强烈联系。具体目标是1）。开发特异于18 q21 -22区域的定制基因阵列，用于表达谱分析和鉴定BPD中具有改变的表达和/或剪接变异的基因; 2）。利用基因芯片技术鉴定BPD患者死后脑组织和新鲜血液中表达改变的基因，并利用更准确的RT-PCR技术验证芯片实验中的显著性发现; 3）.在双相情感障碍家系中，对18 q21 -22的SNPs进行鉴定和基因分型，并使用LD分析来检验等位基因或单倍型与BPD的关联。

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.