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）是一种严重的精神疾病，影响全球1%的人口，并对易感性有很强的遗传影响。最近的遗传学研究，如全基因组关联研究（GWAS）和结构基因组研究已经取得了显着的进展，但留下了相当大的一部分遗传风险无法解释，建议应探索替代模型。我们设计了一个有针对性的测序实验，通过选择编码和调控序列的基因组间隔与高先前的证据参与SZ。我们的目标来自（i）位于SZ相关拷贝数变异（CNV）间隔内的基因，或（ii）在SZ中显示极端转录偏离的基因，总共约600 kb的序列。我们建议从SZ的分子遗传学（MGS）收集测序样本，并从基因组精神病学队列（GPC）中提取序列，从而产生3，181例SZ病例和3，500例匹配对照的大型组合欧洲血统（EA）发现样本。通过将我们的目标限制在一个面积小但可能富含SZ的区域， 相关的低频变异，我们既降低了显著性所需的统计阈值，又经济地允许大样本量，使我们能够最大限度地识别SZ的新关联。然后，我们将在剩余的4，100个SZ病例的GPC EA样本中检查复制的最高命中率，并筛选5，400个对照。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来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组中产生诱导多能干细胞（iPSC）分化的神经元，并对其表型进行表征。如果成功，我们的研究将确定基因，推定的突变，以及这些突变有助于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、有针对性的假设进行测试。所有数据和生物材料将通过指定的NIMH储存库（www.nimhgenetics.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).