Genetics of Early-Onset Major Depression

早发性重度抑郁症的遗传学

• 批准号: 7124617
• 负责人: MYRNA M WEISSMAN
• 金额: $ 51.75万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 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/7124617
• 关键词: African American; behavioral /social science research tag; behavioral genetics; caucasian American; cell line; child abuse; clinical research; cooperative study; disease /disorder onset; family genetics; genetic registry /resource /referral center; genetic susceptibility; genotype; human genetic material tag; human subject; interview; linkage mapping; longitudinal human study; major depression; medical outreach /case finding; mental health information system; parent deprivation

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）：这是对协作R01四年竞争持续建议的第二次修订，以创建大型基于存储库的病例样本，以复发，早期发作的重大抑郁症（MDD-RE）（MDD-RE），并使用位置克隆来识别我们基因组识别区域中抑郁症状基因的抑郁症状基因。 完整的四年项目收集了680个家庭，其中包含927个受影响的兄弟姐妹对（ASP）（MDD-RE诊断模型）和其他受影响的亲戚（Genred I）。盲目的临床数据和用于细胞培养的血液样本被沉积在NIMH存储库中，并被公开。链接细映射已显示在染色体15Q上的全基因组显着连接；在10 cm的基因组扫描中，在三个区域（6p-q，8p，17p）中观察到了暗示性的性别特异性连接，结果是17p染色体接近全基因组意义的结果。六个合作网站现在建议： (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）启动基于存储库的非洲裔美国人（AA）MDD-RE检验，符合相同的临床标准。我们将收集750个AA概率，以及可用的父母和受影响的兄弟姐妹，并与年轻的少数民族共同研究员有关； AA控件将从存储库中获得。添加了霍华德大学的一个网站以领导这项工作。 AA招聘将持续到4年级，以建立存储库样本。 （3）收集有关儿童虐待，忽视和父母损失的数据，主要环境国防部的风险因素； （4）对染色体17p，1q，5q，5q，6p-Q，8p和18Q进行连锁细图研究，以最大程度地证明连锁和狭窄的候选区域。 （5）在15Q候选区域进行连锁不平衡（LD）映射和密集的基因分析研究，并在2,000欧元的案例和2,000个筛选，种族匹配的对照中进行另外一个区域；并使用高通量SNP基因分型方法在600例AA病例中对最重要的基因进行LD精细映射研究，并进行1,000个对照。 拟议的研究将通过鉴定易感性基因，并创建公共集合生物材料和临床数据以及超过1300万SNP基因型来促进对复发模型和相关表型的进一步研究，从而有助于理解这种毁灭性常见疾病。