GENETIC LINKAGE STUDIES IN BIPOLAR DISORDERS

双相情感障碍的遗传连锁研究

• 批准号: 6392787
• 负责人: Francis J McMahon
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-15 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6392787
• 关键词: alcoholism /alcohol abuse; behavioral genetics; bipolar depression; cell line; clinical research; comorbidity; data management; family genetics; gene expression; genetic markers; genetic susceptibility; human genetic material tag; human subject; linkage disequilibriums; linkage mapping; mood disorders; siblings

This application is submitted under the Program Announcement "Collaborative Studies of Mental Disorders." The broad aims are to expand a unique, existing set of pedigrees and test candidate regions for linkage and association with bipolar disorder. For the Johns Hopkins site this represents a revised competing renewal application while for the University of Chicago site this is a new proposal. Together we propose to double the existing family resource by ascertaining an additional 80 moderate-sized families through bipolar I probands with 2 or more siblings affected with recurrent major affective disorders. All participants will be interviewed by trained psychiatrists who have established excellent inter-rater reliability. Diagnoses will be assigned by 2 non-interviewing psychiatrists who review all clinical data. This sample has already proven to be of considerable value to the field. Among clinical findings that have spawned new research directions are our reports of anticipation, parent-of-origin effects, a high prevalence of BPII among the close relatives of the bipolar I probands, and high rates of comorbid panic disorder in a subset of families. This sample provided the first support for previous evidence of linkage to the peri-centromeric region of chromosome 18, the first evidence of linkage to 18q, and the first molecular evidence for a parent-of-origin effect in bipolar disorder. Findings from prospective studies of the 2nd half of this sample demonstrate strikingly high allele-sharing between bipolar II sib pairs at several loci in 18q2l. Exploratory analyses of co- morbid panic disorder and alcoholism have also suggested methods for predicting heterogeneity between bipolar families. In addition to collecting more families, we propose to genotype the existing and additional family sets at candidate regions implicated by a recent genome-wide scan for linkage that has been completed on 68 pedigrees from this sample. We further propose to use standard and innovative linkage and association methods to extract the maximal genetic information needed to locate genes influencing susceptibility to bipolar disorder. This is the most carefully clinically assessed family set in the field. The studies generated from this family resource have already demonstrated its value and have provided testable hypotheses for further work. The enlargement, continued maintenance, and analysis of this unique family resource is important to the field and will form the basis for many future studies.

本申请是根据“精神疾病合作研究”项目公告提交的。“广泛的目标是扩大一个独特的，现有的一套谱系和测试候选地区的联系和关联与双相情感障碍。 对于约翰霍普金斯研究中心，这代表了修订后的竞争性续期申请，而对于芝加哥大学研究中心，这是一项新提案。 总之，我们建议通过确定额外的80个中等规模的家庭，通过双相I先证者与2个或更多的兄弟姐妹患有复发性重大情感障碍，现有的家庭资源增加一倍。 所有受试者将由经过培训的精神科医生进行访谈，这些精神科医生已经建立了良好的评估者间可靠性。 诊断将由2名审查所有临床数据的非访谈精神科医生分配。 该样品已被证明对该领域具有相当大的价值。 在临床发现中，催生了新的研究方向是我们的报告的预期，父母的原产地的影响，高患病率的BPII之间的近亲的双相I先证者，和高比例的共病惊恐障碍的一个子集的家庭。 该样本首次支持了先前关于与18号染色体着丝粒周围区域连锁的证据，首次证明了与18q连锁的证据，并首次提供了双相情感障碍中父母起源效应的分子证据。该样本的后半部分的前瞻性研究结果表明，双极II同胞对在18q2l的几个位点之间具有惊人的高等位基因共享。 对惊恐障碍和酒精中毒共病的探索性分析也提出了预测双相情感障碍家族异质性的方法。 除了收集更多的家庭，我们建议基因型现有的和额外的家庭集在候选区域牵连最近的全基因组扫描连锁，已完成68个家系从这个样本。 我们进一步建议使用标准和创新的连锁和关联方法来提取最大的遗传信息，以定位影响双相情感障碍易感性的基因。 这是该领域最仔细的临床评估家庭。 从这个家庭资源产生的研究已经证明了它的价值，并为进一步的工作提供了可检验的假设。 这种独特的家庭资源的扩大，持续的维护和分析是重要的领域，并将成为许多未来研究的基础。