A computational genomics approach to identify roles of rare genetic variants in psychiatric disorders and gene expression

项目摘要 这是K 01生物医学大数据科学指导职业发展奖的提案。的目标 这项建议是获得生物医学科学的培训，重点是精神疾病，并进行研究， 发现影响人类复杂特征的罕见遗传变异，包括两种精神疾病，双相情感障碍， 精神分裂症（SCZ）。识别这些罕见的变异对生物学和人类都至关重要。 它将有助于阐明这些疾病的遗传基础，并促进治疗方法的发展。最近， 因为下一代测序的成本以比摩尔定律所描述的更快的速度降低， 许多遗传学研究利用全基因组测序（WGS）来确定罕见基因的作用。 人类复杂特征的变异然而，这些研究取得的成功有限，最有可能是由于小 样本量在本提案中，我将分析三个WGS数据集，这些数据集提供了独特的机会来发现 罕见的变种第一个是BP大家系的WGS数据，其中罕见变异可能在某些特定的基因中富集。 大家庭，增加我们发现其影响的机会。第二个是表达数量性状基因座数据， 包含来自Genotype-Tissue Expression（GTEx）倡议的WGS和RNA-Seq。GTEx收集基因 从多种人类组织中表达，这将能够发现罕见变异体对细胞的功能影响。 不同的组织第三部分是两个国家的4,000例BP和SCZ病例对照的WGS数据， 人口普查。在这些人群中，有害的罕见变异可能具有升高的等位基因频率， 这增加了检测其效果的统计能力。为了有效地分析三个WGS数据集，我将 开发一种新的统计方法，并利用我已经开发的方法。这些方法联合收割机 基因中多个罕见变异的影响，以增加统计功效。我将把这些方法应用到三个 WGS数据集用于识别影响精神疾病（BP和SCZ）和基因表达的罕见变异。 虽然我在计算机科学和统计学方面有相当多的知识和专业知识，但我寻求 获得生物医学科学方面的额外培训，特别是在精神疾病和临床研究方面， 解释罕见变异分析的结果并从结果中提取有生物学意义的信息。我会 参加加州大学洛杉矶分校和其他机构提供的几个课程和讲习班，以获得这种培训。这 培训将使我能够设计和领导精神疾病的基因组研究，并发展一个利基， 统计遗传学家这些近期目标将成为我长期职业目标的基础， 了解基因组序列如何影响一个人对疾病的易感性， 治疗。我将由纳尔逊弗雷默博士、乔纳森弗林特博士和乔瓦尼科波拉博士指导，他们是 神经精神疾病和基因组学。他们将为我的教育和研究培训提供指导 整个颁奖期间。

Project Summary This is a proposal for the K01 Mentored Career Development Award in Biomedical Big Data Science. The goal of this proposal is to obtain training in biomedical science with focus on psychiatric disorders, and perform research to discover rare genetic variants that influence human complex traits including two psychiatric disorders, bipolar disorder (BP) and schizophrenia (SCZ). Identifying those rare variants is critical for both biology and human health as it will elucidate the genetic basis of those disorders and facilitate development of treatment. Recently, as the cost of next-generation sequencing decreases at a rate faster than that described by Moore's law for computer chips, many genetic studies are utilizing whole-genome sequencing (WGS) to identify roles of rare variants in human complex traits. However, these studies have had limited success most likely due to the small sample size. In this proposal, I will analyze three WGS data sets that provide unique opportunities to find effect of rare variants. The first is WGS data of large pedigrees with BP in which rare variants may be enriched in a certain large family, increasing our chance to detect their effect. The second is expression quantitative trait loci data that contain WGS and RNA-Seq from Genotype-Tissue Expression (GTEx) initiative. GTEx collected gene expression from multiple human tissues, which would enable discovery of functional effects of rare variants on different tissues. The third is WGS data of 4,000 BP and SCZ case-control samples from two recently bottlenecked populations. Deleterious rare variants may have elevated allele frequency in these populations, which increases statistical power to detect their effect. To effectively analyze the three WGS data sets, I will develop a new statistical approach and also utilize methods that I already developed. These methods combine effects of multiple rare variants in a gene to increase statistical power. I will apply these methods to the three WGS data sets to identify rare variants that influence psychiatric disorders (BP and SCZ) and gene expression. Although I have considerable knowledge and expertise in computer science and statistics, I seek to obtain additional training in biomedical science, especially in psychiatric disorders and clinical research to better interpret results of the rare variant analyses and extract biologically meaningful information from results. I will participate in several courses and workshops offered at UCLA and other institutions to obtain this training. This training will enable me to design and lead genomic studies for psychiatric disorders and to develop a niche as a statistical geneticist. These immediate goals will be the basis for my long-term career goal, which is to enhance understanding of how genome sequences influence one's susceptibility to diseases and to develop personalized treatments. I will be mentored by Drs. Nelson Freimer, Jonathan Flint, and Giovanni Coppola who are experts in neuropsychiatric disorders and genomics. They will provide guidance on my education and research training throughout the award period.