1/2 Targeted Sequencing and Functional Evaluation of Mutations in Schizophrenia

描述(由申请人提供)： 精神分裂症(SZ)是一种严重的精神障碍，影响全球1%的人口，并对易感性有很强的遗传影响。最近对SZ的遗传学研究，如全基因组关联研究和结构基因组研究取得了显著进展，但仍有很大一部分遗传风险未被解释，建议探索替代模式。我们设计了一个有针对性的测序实验，通过在基因组间隔中选择编码和调控序列，并提供了参与SZ的高先验证据。我们的靶点来自(I)驻留在SZ相关拷贝数变异(CNV)区间内的基因，或(Ii)在SZ显示极端转录偏离的基因，总计~600kb的序列。我们建议对SZ的分子遗传学(MGS)收集的样本进行测序，并从基因组精神病学队列(GPC)中提取序列，从而产生一个大型的欧洲血统(EA)发现样本，其中包括3,181名SZ病例和3,500名匹配的对照。通过将我们的目标限制在一个很小但可能是深圳富集区的地区 对于相关的低频变量，我们既降低了显著性所需的统计阈值，又在经济上允许大样本量，使我们能够最大限度地确定SZ的新关联。然后，我们将在剩余的4,100例SZ病例的GPC EA样本中检查复制的最高命中率，并筛选5,400名对照。此外，我们建议通过对我们最有希望的候选人进行功能评估，增加另一个信息维度。为了实现这一目标，在随后的初步探索性工作中，我们将从携带相关突变的患者和对照中培养并鉴定诱导多能干细胞(IPSC)分化的神经元。如果成功，我们的研究将确定基因、假定的突变以及这些突变导致SZ病理的作用机制。通过这种方式，我们期望完善我们对SZ的理解，并提出新的、重点突出的假设以供检验。所有数据和生物材料将通过指定的NIMH储存库(www.nimhgentics.org)和DBGaP(dbgap.ncbi.nlm.nih.gov)迅速共享。

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a severe psychiatric disorder that affects 1% of the population worldwide and has a strong genetic influence on susceptibility. Recent genetic investigations of SZ, such as genome-wide association studies (GWAS) and structural genomic studies have made remarkable progress but leave a substantial part of the genetic risk unexplained, suggesting alternative models should be explored. We have designed a targeted sequencing experiment, by selecting coding and regulatory sequence in genomic intervals with high prior evidence for involvement in SZ. Our targets come from (i) genes that reside within SZ- associated copy number variant (CNV) intervals, or (ii) genes that show extreme transcriptional departures in SZ, for a total of ~600kb of sequence. We propose sequencing sample from the Molecular Genetics of SZ (MGS) collection and extracting sequence from the Genomic Psychiatry Cohort (GPC), resulting in a large, combined European ancestry (EA) discovery sample of 3,181 SZ cases and 3,500 matched controls. By limiting our target to a region that is small but likely enriched for SZ associated low frequency variants, we both lower the statistical threshold required for significance, and economically allow for a large sample size, giving us maximal power to identify new associations for SZ. We will then examine top hits for replication in the remaining GPC EA sample of 4,100 SZ cases and screened 5,400 controls. In addition, we propose adding another dimension of information, by functional evaluation of our most promising candidates. To accomplish this goal, in subsequent initial, exploratory work, we will generate and phenotypically characterize induced pluripotent stem cell (iPSC)-differentiated neurons from patients harboring associated mutations and from controls. If successful, our study will identify genes, putative mutations, and a mechanism of action by which those mutations contribute to SZ pathology. In this way we expect to refine our understanding of SZ and advance new, focused hypotheses to be tested. All data and biological materials will be rapidly shared through the designated NIMH repository (www.nimhgenetics.org) and dbGaP (dbgap.ncbi.nlm.nih.gov).