The Bipolar Genome Study

双相基因组研究

• 批准号: 8495419
• 负责人: David W Craig
• 金额: $ 66.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495419
• 关键词: Affect; Alleles; Bar Codes; Biological; Bipolar Disorder; Candidate Disease Gene; Collection; Communities; Complex; DNA Resequencing; Data; Deposition; Development; Dideoxy Chain Termination DNA Sequencing; Disease; Employee Strikes; Event; Exons; Extended Family; Family; Family Study; Frequencies; Future; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genomics; Goals; Heritability; Individual; Individual Differences; Link; Maps; Mental disorders; Mutation; National Institute of Mental Health; Nucleic Acid Regulatory Sequences; Patients; Pattern; Play; Population; Predisposition; Resources; Risk; Role; Sampling; Single Nucleotide Polymorphism in Coding Sequence; Staging; Susceptibility Gene; Technology; Testing; Twin Studies; Validation; Variant; Weight; base; case control; disorder risk; exome sequencing; genetic linkage analysis; genetic pedigree; genetic variant; genome sequencing; genome wide association study; member; next generation; next generation sequencing; novel; proband; promoter; repository; segregation; success; tool

DESCRIPTION (provided by applicant): Bipolar disorder (BD) is a serious psychiatric disorder affecting 1-3% of the population. Though family and twin studies support strong heritability, progress towards identifying specific genes has been slow. Our consortium has studied the genetics of bipolar disorder for over 20 years, and collected one of the largest samples of bipolar families and cases in the world. Though genomewide association studies (GWAS) have identified some genes and a significant polygenic component, these mapping approaches have had only limited success. It has been proposed that this "missing heritability" is transmitted in part through a large number of rare variants of strong genetic effect. Such rare variants might range in frequency from uncommon (<1%) to extremely rare (private mutations), and may include a variety of types including SNPs, indels and CNVs. GWAS, even with next-generation chips, would have limited power to detect such rare variation, and exome sequencing misses many structural variants. Fortunately, next generation sequencing technology has advanced at a staggering pace in the last few years, making whole genome sequencing a practical and affordable tool. We propose to make use of our large collection of families with bipolar disorder and a recent large linkage study conducted by our consortium, in combination with whole genome sequencing and targeted sequencing, to identify rare variants of strong effect that play a causative role in BD. Using our recent linkage study, we have identified 52 families with strong evidence for linkage and selected one member from each family most likely to harbor causative variants. In Aim 1, we will sequence the entire genome of these 52 subjects in order to identify rare variants of strong effect in the genomic regions in each case for which there is evidence of linkage; 12 regions in all. Variants of predicted strong functional effect will be sought in the bet linkage region for each family. In Aim 2, these candidate functional rare variants will be validated by Sanger sequencing and examined for cosegregation with disease in their family. In Aim 3, these variants will be used to select a prioritized list of candidate genes that will then undergo targeted sequencing in a sample of 1,500 BD cases and 1,500 controls. We hypothesize that additional rare variants of strong functional effect will be identified in those genes that convey genetic vulnerability to BD. We will use a sophisticated collapsed variant set analysis approach to test the hypothesis that these genes carry a greater mutational burden in the BD cases as compared to controls. All sequencing data will be made available to the scientific community and will provide an invaluable resource for future studies. The identification of vulnerability genes and mutations in BD will contribute to our understanding of its biological mechanism and facilitate the development of new treatments.

描述（由申请人提供）：双相情感障碍（BD）是一种严重的精神疾病，影响了1-3％的人口。尽管家庭和双胞胎研究支持强大的遗传力，但识别特定基因的进展却很慢。我们的财团研究了20多年的躁郁症遗传学，并收集了世界上最大的双极家庭和病例样本之一。尽管全基因组关联研究（GWAS）已经鉴定出一些基因和重要的多基因成分，但这些映射方法的成功仅限。有人提出，这种“缺失的遗传力”部分通过大量强大遗传效应的稀有变体传播。这种罕见的变体的频率可能从罕见（<1％）到极为罕见的（私人突变），并且可能包括各种类型的SNP，Indels和CNV。即使使用下一代芯片，GWAS也将具有有限的检测到这种罕见变化的能力，而外显子组测序会错过许多结构变体。幸运的是，在过去的几年中，下一代测序技术以惊人的速度提高，使整个基因组测序成为实用且负担得起的工具。 我们建议利用我们的大量躁郁症家族以及我们的财团进行的最新大型连锁研究，结合整个基因组测序和靶向测序，以识别出在BD中发挥致命作用的稀有效果的罕见变体。使用我们最近的链接研究，我们已经确定了52个家庭，有很强的联系证据，并从每个家庭中选择了一个最有可能具有因果变体的成员。在AIM 1中，我们将对这52名受试者的整个基因组进行测序，以便在每种情况下都有联系证据的基因组区域中稀有效果的罕见变体。总共12个地区。每个家庭的BET连锁区域将寻求预测的强大功能效应的变体。在AIM 2中，这些候选功能性稀有变体将通过Sanger测序来验证，并在其家庭中检查与疾病的cosegregation。在AIM 3中，这些变体将用于选择候选基因的优先列表，然后在1,500个BD病例和1,500个对照的样本中进行靶向测序。我们假设在传达BD遗传脆弱性的基因中将确定其他具有强功能效应的稀有变体。我们将使用复杂的折叠变体集分析方法来检验以下假设：与对照组相比，这些基因在BD病例中承担更大的突变负担。所有测序数据都将提供给科学界，并为将来的研究提供宝贵的资源。标识 BD中的脆弱性基因和突变将有助于我们对其生物学机制的理解，并促进新疗法的发展。