Modeling Dimensionality and Genetic Heterogeneity in Schizophrenia

 描述(申请人提供)：精神分裂症(深圳)是一个重大的和昂贵的公共卫生负担。最近，我们通过第一次全基因组关联研究(Gwas)见证了对SZ病因机制的第一次分子洞察力的出现，该研究具有足够的病例对照样本量来检测等位基因效应。重要的是，多基因特征，包括全基因组范围内重要的小效应常见遗传变异，已经被清楚地证明影响SZ风险。明确定义的危险因素的可获得性使得首次有可能解决关于SZ的遗传结构及其组成表型和内表型的几个关键问题。这项K01提案的总体目标是：1)在大病例、高密度SZ家系和前驱年龄的GWAS样本中测试维度SZ和分裂型表型的多基因风险分数预测，以及2)与精神病学基因组联合会的领导人一起开发和测试创新的统计方法，以识别和表征SZ的“遗传亚型”。这项建议为候选人勾画了一系列培训和研究目标，结合了表型评估、统计遗传学和分子遗传学的优势，并结合了反映广泛遗传风险的样本。候选人将利用以前在分裂类型和临床风险评估方面的专业知识，以及在维度特征的家族遗传方面的专业知识，来建立 翻译研究计划，其中将使用统计遗传/生物信息学技术进行基因亚型分析，以产生在人类基因组数据中进一步探索的有前途的候选者。基于经验的遗传亚型方法将在迄今为止最大的深圳病例样本中开发和测试，亚型将根据维度表型特征进行表征。维度症状亚型分析中的最高基因座命中将在对死后SZ脑中差异基因表达的二次分析中得到验证。这将允许在SNP和基因水平上进行详细的功能分析，并将为应聘者提供统计和分子遗传学方法方面的实质性培训。该机构的环境非常适合候选人在深圳特区研究中开发一个综合项目的目标，拟议中的研究是通过结合临床、统计学、分子和翻译方法来促进对深圳特区的了解的重要贡献，与NIMH的使命一致。

 DESCRIPTION (provided by applicant): Schizophrenia (SZ) represents a significant and costly public health burden. Recently, we have witnessed the emergence of the first molecular insights into the etiopathogenic mechanisms of SZ, via the first genome-wide association studies (GWAS) with sufficient case-control sample sizes to detect allelic effects. Importantly, a polygenic signature, which includes genome-wide significant common genetic variants of small effect, has been clearly demonstrated to influence SZ risk. The availability of well-defined risk factors makes it possible, for the first time, to address several critical questions about the genetic architecture of SZ and its component phenotypes and endophenotypes. The overarching goals of this K01 proposal are 1) to test polygenic risk score prediction of dimensional SZ and schizotypy phenotypes across large case, high-density SZ pedigree, and prodromal-aged GWAS samples, and 2) to develop and test, with leaders of the Psychiatric Genomics Consortium, innovative statistical methods to identify and characterize "genetic subtypes" of SZ. This proposal delineates a series of training and research goals for the candidate that incorporates strengths from phenotypic assessment, statistical genetics, and molecular genetics and combines samples reflecting a broad range of genetic risk. The candidate will capitalize on previously established expertise in schizotypy and clinical risk assessment, as well as expertise in the familial transmission of dimensional traits, to establish a program of translational research wherein the application of statistical genetic/bioinformatic techniques to genetic subtyping analyses will be used to generate promising candidates for further exploration in human genomic data. Empirically-based genetic subtyping methods will be developed and tested in the largest SZ case sample to date, and subtypes will be characterized with respect to dimensional phenotypic traits. Top loci hits in subtype analyses of dimensional symptoms will be validated in secondary analyses of differential gene expression in post-mortem SZ brain. This will allow for a detailed analysis of function at both the SNP and gene levels, and will provide the candidate with substantive training in both statistical and molecular genetics methods. The institutional environment is ideal for the candidate's goal of developing a comprehensive program in SZ research, and the proposed research represents an important contribution toward advancing the understanding of SZ through a combination of clinical, statistical, molecular, and translational methods, consistent with the mission of the NIMH.