Finding causal variants within schizophrenia risk loci

寻找精神分裂症风险基因座内的因果变异

• 批准号: 9069125
• 负责人: Jin Peng Szatkiewicz
• 金额: $ 63.66万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069125
• 关键词: 16p11.2; 22q11.21; Affect; Algorithms; Alleles; Arts; Bioinformatics; Biological; Brain Diseases; Cataloging; Catalogs; Clinical Treatment; Communities; Complex; Computer Simulation; Copy Number Polymorphism; Custom; DNA Resequencing; Data; Diploidy; Disease; Ensure; Etiology; European; Expenditure; Future; Genes; Genetic; Genomic Segment; Genotype; Goals; Haploidy; Health; High-Throughput Nucleotide Sequencing; Human Genetics; Literature; Methods; Molecular Biology; Morbidity - disease rate; Mutation; Neurosciences; Perception; Predisposition; Preventive; Public Health; Quality Control; Reading; Regulator Genes; Regulatory Element; Research; Resources; Risk; Sampling; Schizophrenia; Services; Signal Transduction; Structure; Surveys; Targeted Resequencing; Technology; Testing; Thinking; Treatment Protocols; Variant; Work; base; case control; cost; dosage; exome sequencing; genetic variant; genome wide association study; genome-wide; improved; meetings; mortality; nano-string; novel; programs; risk variant

 DESCRIPTION (provided by applicant): Schizophrenia is highly heritable and the cause of substantial morbidity, mortality, and personal and societal costs. To increase our understanding of the biological basis of schizophrenia, it is essential to identify precise causal mutations that influence risk. GWAS have been remarkably successful in identifying genomic regions harboring common SNPs associated with schizophrenia. The most recent PGC analysis yielded 128 genome- wide significant loci and this number will likely increase. However, the causative variants underlying nearly all GWAS loci have proven elusive. Existing imputation resources are not optimized for GWAS loci. The overarching goal of this proposal is to identify causative mutations within schizophrenia GWAS loci. Common risk loci resulting from changes in copy number (i.e., copy number polymorphism, or CNP) are attractive casual mutations. CNPs that reside within GWAS loci (i.e., "tagged" by the associated SNPs) can alter the dosage or structure of regulatory elements and genes and exert functional impact to drive the observed association with SCZ. Multiple examples are in the literature. The contribution of CNPs to schizophrenia is unknown because large-scale surveys of CNPs are infrequent. CNPs are inaccessible to most current methods, and CNP imputation methods are underdeveloped. Since CNPs are highly plausible but largely unexplored, we propose to deeply sequence schizophrenia samples at the PGC GWAS loci to identify CNPs and uncommon SNP/indels, and then impute them into very large samples to test for association with very high power with schizophrenia. Identifying uncommon SNP/indels maximizes expenditure of the proposed study. Successful completion of the proposed work will enhance our understanding of biological mechanisms underlying the etiology of schizophrenia. If we can identify even a few CNPs or uncommon SNP/indels altering schizophrenia risk, it will represent an important advance in the field. Any CNP association is likely to have immediate biological relevance and amenability to current molecular biology and neuroscience methods. Furthermore, these schizophrenia-associated GWAS loci have never been deeply sequenced in the world-literature. The targeted resequencing data, the imputation reference, and CNP imputation methods generated from this R01 will be useful resources for the human genetics community. These data will also ensure that the community's forthcoming functional work on these risk loci is focused on the most promising variants.

 描述（由申请人提供）：精神分裂症具有高度遗传性，是导致大量发病、死亡以及个人和社会成本的原因。为了加深我们对精神分裂症生物学基础的了解，有必要确定导致其发生的精确因果突变。 GWAS 在识别含有与精神分裂症相关的常见 SNP 的基因组区域方面取得了巨大成功，最新的 PGC 分析产生了 128 个全基因组显着基因座，而且这个数字可能还会增加，但是，几乎所有 GWAS 基因座的致病变异都已得到证实。现有的插补资源并未针对 GWAS 位点进行优化 该提案的首要目标是确定精神分裂症 GWAS 中的致病突变。拷贝数变化（即拷贝数多态性或 CNP）引起的常见风险基因座是 GWAS 基因座内有吸引力的偶然突变（即由相关 SNP“标记”），可以改变药物的剂量或结构。文献中有多个 CNP 对精神分裂症的贡献，因为对 CNP 的大规模调查尚不清楚。大多数现有方法无法获得 CNP，并且 CNP 插补方法尚未开发，因此我们建议对 PGC GWAS 位点的精神分裂症样本进行深度测序，以识别 CNP 和不常见的 SNP/indel，然后进行插补。将它们分成非常大的样本，以测试与精神分裂症的高功效关联，从而最大限度地提高拟议研究的支出。成功完成拟议的工作将增强我们对精神分裂症病因学背后的生物学机制的理解，如果我们能够识别出一些改变精神分裂症风险的 CNP 或不常见的 SNP/插入缺失，那么这将代表该领域的重要进展。可能与当前的分子生物学和神经科学方法具有直接的生物学相关性和适应性。此外，这些与精神分裂症相关的 GWAS 位点从未在世界文献中进行过深入测序。从 R01 生成的目标重测序数据、插补参考和 CNP 插补方法将为人类遗传学界提供有用的资源，这些数据还将确保该界即将针对这些风险位点开展的功能性工作集中在最有希望的变异上。