Whole Genome Sequencing of Multiplex Bipolar Families

多重双相家庭的全基因组测序

基本信息

批准号：
8429869
负责人：
Jessica Ross
金额：
$ 7.83万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-20 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8429869
关键词：
Accounting Adoption Affect Alleles Area Biotechnology Bipolar Disorder Case-Control Studies Code Collaborations Computer software Contracts DNA Data Data Linkages Diagnosis Dideoxy Chain Termination DNA Sequencing Disease European Family Family member Funding Future Gene Mutation Generations Genes Genetic Genetic Predisposition to Disease Genome Genotype Heritability Heterogeneity Individual Inherited Lead Manic Maps Mental Depression Morbidity - disease rate National Institute of Mental Health Neurobiology Nucleic Acid Regulatory Sequences Population Predisposition Price Promoter Regions Publishing RNA Splicing Sampling San Francisco Site Susceptibility Gene Twin Multiple Birth Untranslated Regions Variant Work base case control cost design exome genetic pedigree genome sequencing genome wide association study genome-wide linkage interest member mortality neuropsychiatry next generation novel proband programs segregation

项目摘要

DESCRIPTION (provided by applicant): Bipolar I disorder (BPI) is a severe neuropsychiatric disorder that afflicts approximately 1% of most populations. Pivotal neurobiological underpinnings of BPI have yet to be unraveled but family, twin and adoption studies carried out over the past half century indicate that hereditary factors underlie at least 80% of disease variance. Recent genome wide association (GWA) studies of BPI indicate that common variants with small effect sizes explain no more than 3% of the genetic liability. The "missing heritability is thought to be explained by many common variants with "very small" effect sizes and/or rare variants with relatively large effect sizes. Families with a large percentage of affected individuas in more than one generation are likely to contain coding or regulatory variants with large effect sizes. This study focuses on identifying rare susceptibility variants in two multigenerational BPI pedigrees of European ancestry, each containing at least 7 BPI cases across at least two generations, ascertained through the NIMH Genetics Initiative. These families have been recently genotyped, and there are linkage data that will help prioritize the search for rare variants. We have selected 3 cases for whole genome sequencing in each family. The work will be contracted out to a private biotechnology company at a cost of no more 4.0K per genome. We will prioritize all rare variants shared by the 3 BPI cases in the exome and proximal regulatory and promoter regions. A novel analytic program, ANNOVAR, will be used for prioritizing rare variants. We will check for co-segregation of potential disease predisposing rare variants using all affected family members with DNA available, and for the variants that remain, we will apply for funding to carry out "gene-based" case control studies in unrelated affecteds and controls. PUBLIC HEALTH RELEVANCE: Bipolar disorder, also termed Manic-depression, is a genetically based neuropsychiatric disorder that affects approximately 1% of the population and causes considerable morbidity and mortality. Identification of genes predisposing to disease will help unravel the neurobiology of illness and lead to better diagnoses and treatment of this disabling disorder.

描述（由申请人提供）：双相情感障碍（BPI）是一种严重的神经精神疾病，大约占大多数人群的1％。 BPI的关键神经生物学基础尚未揭露，但是在过去的半个世纪进行了家庭，双胞胎和收养研究表明，遗传因素至少是疾病差异的80％的基础。最近对BPI的基因组广泛关联（GWA）的研究表明，具有较小效应量的常见变体可解释遗传责任的3％。 The "missing heritability is thought to be explained by many common variants with "very small" effect sizes and/or rare variants with relatively large effect sizes. Families with a large percentage of affected individuas in more than one generation are likely to contain coding or regulatory variants with large effect sizes. This study focuses on identifying rare susceptibility variants in two multigenerational BPI pedigrees of European ancestry, each containing at least 7在NIMH遗传学的范围内确定了至少两个世代的BPI。外显子和近端调节和启动子区域中的病例将用于优先考虑稀有变体。我们将检查易于罕见的潜在疾病的共隔离使用所有受影响家庭成员的DNA可用的变体，对于剩余的变体，我们将申请资金，以在无关受影响和控制措施中进行“基于基因”的案例控制研究。公共卫生相关性：双相情感障碍，也称为躁狂抑郁症，是一种基于遗传性的神经精神疾病，影响了大约1％的人口，并引起相当大的发病率和死亡率。鉴定易感疾病的基因将有助于揭示疾病的神经生物学，并导致更好的诊断和治疗这种残疾疾病。