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“精神障碍合作研究”计划公告提交的。 广泛的目标是扩展一套独特的、现有的谱系，并测试候选区域与双相情感障碍的联系和关联。 对于约翰·霍普金斯大学网站来说，这代表了修订后的竞争性更新申请，而对于芝加哥大学网站来说，这是一个新提案。 我们共同提议通过有 2 个或更多兄弟姐妹患有复发性严重情感障碍的双相 I 先证者确定另外 80 个中等规模家庭，从而使现有家庭资源增加一倍。 所有参与者都将接受经过培训的精神科医生的访谈，他们已建立了良好的评估者间可靠性。 诊断将由 2 名非访谈精神科医生审查所有临床数据来分配。 该样本已被证明对该领域具有相当大的价值。 催生新研究方向的临床发现包括预期、父母效应、I型双相情感障碍先证者近亲中BPII的高患病率以及部分家庭中共病恐慌症的高发生率。 该样本为先前与 18 号染色体周围着丝粒区域连锁的证据提供了第一个支持，与 18q 连锁的第一个证据，以及双相情感障碍中亲本效应的第一个分子证据。该样本后半部分的前瞻性研究结果表明，双相 II 同胞对之间在 18q2l 的几个位点上具有惊人的高等位基因共享性。 对共病恐慌症和酗酒的探索性分析也提出了预测双相家庭之间异质性的方法。 除了收集更多的家族之外，我们还建议对候选区域中现有的和额外的家族集进行基因分型，这些候选区域是最近在该样本的 68 个谱系上完成的全基因组连锁扫描所涉及的。 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定位影响双相情感障碍易感性的基因所需的最大遗传信息。 这是该领域经过最仔细的临床评估的家庭组。 从这一家庭资源中得出的研究已经证明了其价值，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、持续维护和分析对该领域很重要，并将构成许多未来研究的基础。