Genetics of Early-Onset Depression

早发性抑郁症的遗传学

• 批准号: 7263221
• 负责人: DOUGLAS Frederick LEVINSON
• 金额: $ 37.31万
• 依托单位: STANFORD UNIVERSITY
• 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/7263221
• 关键词: 15q; 17p; 18q; Adult; Affect; African; African American; Bioinformatics; Biological; Blinded; Blood specimen; Candidate Disease Gene; Case-Control Studies; Cell Line; Cells; Child Abuse; Chromosomes; Clinical; Clinical Data; Collection; Cultured Cells; Data; Databases; Deposition; Diagnosis; Diagnostic; Disease; Ethnic Origin; European; Family; Family history of; Genes; Genetic; Genome; Genome Scan; Genotype; Individual; Interview; Investigation; Lead; Linkage Disequilibrium; Linkage Disequilibrium Mapping; Location; Major Depressive Disorder; Maps; Mental Depression; Methods; Minority; Modeling; National Institute of Mental Health; Parents; Phenotype; Platelet Factor 4; Predisposition; Recruitment Activity; Recurrence; Relative (related person); Research Design; Research Personnel; Risk Factors; SNP genotyping; Sampling; Sampling Studies; Series; Siblings; Single Nucleotide Polymorphism Map; Site; Susceptibility Gene; Universities; Validation; base; case control; chromosome 5q loss; early childhood; early onset; follow-up; genetic pedigree; indexing; male; neglect; positional cloning; proband; repository; research study; sex

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R 01合作四年竞争延续提案的第二次修订，旨在创建复发性早发性重度抑郁症（MDD-RE）病例的大型基于储存库的样本，并使用定位克隆来识别我们基因组扫描中显著连锁区域中的抑郁症易感基因。 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）和其他受影响的亲属（GenRED I）。用于细胞培养的盲态临床数据和血液标本存放在NIMH储存库中，并正在公开。连锁精细作图显示15号染色体q上存在全基因组显著连锁;在10 cM基因组扫描中，在3个区域（6p-q，8 p，17 p）观察到暗示性的性别特异性连锁，其中17 p上的结果接近全基因组显著性。六个协作地点现在提议： (1)收集（在第1-3年期间）另外1，350个符合相同标准（包括有受影响同胞的证据）的欧洲血统（EUR）MDD-RE先证者（GenRED II），以创建2，000个EUR MDD-RE病例的总储存库样本，加上来自可用父母、未受影响同胞和男性-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先证者的储存库收集。我们将收集750个AA先证者加上可用的父母和受影响的兄弟姐妹，与年轻的少数民族共同研究者的参与; AA控制将可从存储库。霍华德大学的一个网站已被添加到领导这一努力。AA招聘将持续到第四年，以构建存储库样本。 (3)收集关于儿童期虐待和忽视以及失去父母、主要环境MOD风险因素的数据; (4)对染色体17 p、1 q、5 q、6p-q、8 p和18 q进行连锁精细定位研究，以最大限度地提供连锁证据并缩小候选区域。 (5)在2，000个欧元病例和2，000个筛选的种族匹配对照中，在15 q候选区域和另一个区域进行连锁不平衡作图和密集基因分析研究;并对600例AA患者的主要基因进行LD精细定位研究（N在4年级初可用）和1，000个对照，使用高通量SNP基因分型方法来识别抑郁症易感基因。 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的公共集合以及超过1300万个SNP基因型，以促进对复发性MOD和相关表型的进一步研究，从而有助于理解这种毁灭性的常见疾病。