Genetics of Early-Onset Depression

早发性抑郁症的遗传学

• 批准号: 7124662
• 负责人: WILLIAM Bradford LAWSON
• 金额: $ 26.01万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-22 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7124662
• 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合作的四年竞争延续方案的第二次修订，该方案旨在创建一个基于大型存储库的复发、早发性严重抑郁障碍(MDD-RE)病例样本，并使用位置克隆来识别我们基因组扫描中显著连锁区域的抑郁症易感基因。 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诊断模式)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保存在NIMH储存库中，并正在公布。连锁精细定位在染色体15q上显示了全基因组显著连锁；在10 cM基因组扫描中，在三个区域(6p-q、8p、17p)上观察到了提示的性别特异性连锁，染色体17p上的结果接近全基因组意义。六个协作站点现在提议： (1)(在1-3年)收集符合相同标准(包括有受影响兄弟姐妹的证据)的另外1,350名欧洲血统MDD-RE先证者(Genred II)，以创建2,000例EUR MDD-RE病例的总资料库样本，外加来自可获得的父母、未受影响的同胞和男性-男性ASP的细胞系/DMA。 (2)启动符合相同临床标准的非裔美国人(AA)MDD-RE先证者的资料库收集。我们将收集750名再生障碍性贫血先证者，加上可用的父母和受影响的兄弟姐妹，年轻的少数族裔协查人员参与其中；再生障碍性贫血对照将从储存库中获得。霍华德大学增加了一个网站来领导这项工作。AA招聘将持续到第4年，以建立储存库样本。 (3)收集儿童虐待、忽视和父母丧失的数据，这些都是主要的环境MOD风险因素； (4)开展染色体17p、1q、5q、6p-q、8p和18q的连锁精细定位研究，以最大限度地提供连锁证据，缩小候选区域。 (5)在2,000例EUR病例和2,000名筛选的种族匹配对照中，对15q候选区域和一个额外区域进行连锁不平衡(LD)定位和密集的基因分析研究；在600例再障患者(N在第4年初获得)和1,000名对照中，使用高通量SNP基因分型方法，对最重要的基因进行LD精细定位研究，以确定抑郁症的易感基因。拟议的研究将通过识别易感基因，并通过创建生物材料和临床数据以及1300多万个SNP基因型的公共集合，促进对反复发作的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。