Genetics of Early-Onset Depression

早发性抑郁症的遗传学

• 批准号: 6988212
• 负责人: William Henry Coryell
• 金额: $ 20.65万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988212
• 关键词: African American; behavioral genetics; bioinformatics; biotechnology; clinical research; cooperative study; data collection methodology /evaluation; disease /disorder onset; family genetics; gene expression; genetic mapping; genetic screening; genetic susceptibility; genotype; high throughput technology; human genetic material tag; human subject; interview; linkage disequilibriums; linkage mapping; major depression; molecular cloning; patient /disease registry; phlebotomy

DESCRIPTION (provided by applicant): This is a second revision of a collaborative R01 four-year competing continuation proposal to create a large repository-based sample of cases with recurrent, early-onset major depressive disorder (MDD-RE), and to use positional cloning to identify depression susceptibility genes in regions of significant linkage in our genome scan. The completed four-year project collected 680 families containing 927 affected sibling pairs (ASPs) (MDD-RE diagnostic model) and additional affected relatives (GenRED I). Blinded clinical data and blood specimens for cell culture were deposited in the NIMH repository and are being made public. Linkage fine-mapping has demonstrated genome-wide significant linkage on chromosome 15q; in the 10 cM genome scan, suggestive sex-specific linkage was observed in three regions (6p-q, 8p, 17p), with the result on chromosome 17p approaching genome-wide significance. Six collaborating sites now propose to: (1) Collect (during Years 1-3) an additional 1,350 European-ancestry (EUR) MDD-RE probands (GenRED II) meeting identical criteria (including evidence of having an affected sibling) to create a total repository sample of 2,000 EUR MDD-RE cases, plus cell lines/DMA from available parents, unaffected sibs and male-male ASPs. (2) Initiate a repository-based collection of African-American (AA) MDD-RE probands meeting the same clinical criteria. We will collect 750 AA probands plus available parents and affected siblings, with involvement of young minority co-investigators; AA controls will be available from the repository. A site at Howard University has been added to lead this effort. AA recruitment will continue through Year 4 to build the repository sample. (3) Collect data on childhood abuse and neglect and parental loss, major environmental MOD risk factors; (4) Carry out linkage fine-mapping studies of chromosomes 17p, 1q, 5q, 6p-q, 8p and 18q to maximize evidence for linkage and to narrow candidate regions. (5) Carry out linkage disequilibrium (LD) mapping and intensive gene analysis studies in the 15q candidate region and one additional region in 2,000 EUR cases and 2,000 screened, ethnically-matched controls; and carry out LD fine-mapping studies in the most significant genes in 600 AA cases (the N available early in Year 4) and 1,000 controls, using high-throughput SNP genotyping methods, to identify a depression susceptibility gene. The proposed studies will contribute to the understanding of this devastating common disorder by identifying susceptibility genes, and by creating a public collection of biological materials and clinical data, as well as over 13 million SNP genotypes, to facilitate further investigation of recurrent MOD and related phenotypes.

描述（由申请人提供）：这是 R01 为期四年的竞争性延续提案的第二次修订，旨在创建一个基于存储库的大型复发性早发性重度抑郁症 (MDD-RE) 病例样本，并使用定位克隆来识别在我们的基因组扫描中显着连锁的区域中的抑郁易感性基因。 已完成的四年项目收集了 680 个家庭，其中包括 927 对受影响的兄弟姐妹 (ASP)（MDD-RE 诊断模型）和其他受影响的亲属 (GenRED I)。用于细胞培养的盲法临床数据和血液样本已存放在 NIMH 存储库中并正在公开。连锁精细作图已证明染色体 15q 上全基因组的显着连锁；在 10 cM 基因组扫描中，在三个区域（6p-q、8p、17p）观察到暗示性的性别特异性连锁，染色体 17p 上的结果接近全基因组显着性。六个合作网站现提议： (1) 收集（在第 1-3 年期间）另外 1,350 名符合相同标准（包括有受影响兄弟姐妹的证据）的欧洲血统 (EUR) MDD-RE 先证者 (GenRED II)，以创建 2,000 欧元 MDD-RE 病例的总存储库样本，以及来自可用父母、未受影响同胞和男性 ASP 的细胞系/DMA。 (2) 启动基于存储库的符合相同临床标准的非裔美国人 (AA) MDD-RE 先证者收集。我们将收集 750 名 AA 先证者以及可用的父母和受影响的兄弟姐妹，并邀请年轻的少数族裔共同调查人员参与； AA 控件可从存储库中获取。霍华德大学的一个站点已被添加来领导这项工作。 AA 招募将持续到第四年，以构建存储库样本。 (3) 收集有关儿童期虐待和忽视、父母失去、主要环境MOD危险因素的数据； (4) 对染色体17p、1q、5q、6p-q、8p和18q进行连锁精细作图研究，以最大限度地增加连锁证据并缩小候选区域。 (5) 在 2,000 个 EUR 病例和 2,000 个筛选的种族匹配对照的 15q 候选区域和一个附加区域中进行连锁不平衡 (LD) 作图和深入基因分析研究；并使用高通量SNP基因分型方法，对600个AA病例（第4年早期可用的N）和1,000个对照中最重要的基因进行LD精细定位研究，以确定抑郁症易感基因。 拟议的研究将通过识别易感基因、创建生物材料和临床数据以及超过 1300 万个 SNP 基因型的公共集合，促进对复发性 MOD 和相关表型的进一步研究，从而有助于了解这种毁灭性的常见疾病。