Understanding the genetic architecture of schizophrenia in Chinese population

描述（由申请人提供）：精神分裂症是一种严重的精神障碍，具有显著的遗传效应。然而，遗传因素的性质和身份仍然难以捉摸。最近的全基因组关联研究（GWASs）已经取得了实质性的进展，确定了几个有希望的候选基因的共同变异。然而，这些候选者只占观察到的遗传性的一小部分。最近，测序和拷贝数变异（CNV）分析记录了许多与该疾病风险相关的罕见新生突变。结合我们从GWASs中学到的东西，很明显，常见和罕见的变异都会导致精神分裂症的遗传风险。我们目前对精神分裂症的认识绝大多数来自于对高加索人群的研究。在该领域，对其他种族的调查有限，对人口之间的差异缺乏系统的检查是显而易见的。这些缺陷可能会阻碍我们对这种疾病病因的理解。在响应申请AI- 12-021“美中生物医学合作研究项目（R01）”的请求中，我们提出了旨在了解汉族人群精神分裂症遗传结构的研究，并调查汉族人群和高加索人群之间共同的和种族特异性的危险因素。我们的目标是：1；对140个有多个患病个体的汉族核家庭进行外显子组测序，以发现易患该疾病的单核苷酸变异（snv）和拷贝数变异（cnv）。我们计划使用父母双方（受影响或未受影响），两个受影响和一个未受影响的兄弟姐妹以及一个父母，两个受影响和一个未受影响的兄弟姐妹的家庭。使用有患病和未患病兄弟姐妹的家庭，使我们能够同时发现和描述传播和新生的风险变异。家庭中未受影响的兄弟姐妹比一般人群的受试者更好地控制，因为他们可以帮助区分家庭中观察到的许多良性变异和潜在的病理变异。2. 对5000例病例和5000例对照汉族样本进行基因型分析，以确定上述目标1中发现的100种最有希望的风险变异是否与SCZ相关。我们将应用一套复杂的统计，生物信息学和功能过滤器来选择最有前途的snv。我们将重点关注那些具有潜在功能后果的罕见变异（包括新生变异），以及发生在相同基因和生物学途径中多个位点的变异。3. 利用来自高加索人和汉族人群的GWAS数据集进行比较分析，以估计两个人群之间的遗传风险重叠，并发现和表征共享和种族特异性风险基因。我们建议采用多基因分析的方法来研究PGC和中国GWASs的相关性，以估计这些人群之间危险因素的重叠，并研究这两个民族的SCZ遗传结构。

DESCRIPTION (provided by applicant): Schizophrenia is a severe mental disorder with significant genetic effects. However, the nature and the identity of the genetic factors remain elusive. Recent genome-wide association studies (GWASs) have made substantial progress, identifying several promising candidate genes with common variants. However, these candidates only account for a small proportion of observed heritability. More recently, sequencing and copy number variation (CNV) analyses have documented many rare de novo mutations associated with the risks to this disorder. Combined with what we have learned from GWASs, it is clear that both common and rare variants contribute to genetic risks to schizophrenia. Our current knowledge of schizophrenia is overwhelmingly derived from the study of Caucasian populations. The limited investigations of other ethnicities and the lack of systematic examination of the differences between populations are noticeable in the field. These weaknesses may impede our understanding of the etiology of the disorder. In responding to the request for application AI- 12-021 "U.S.-China Program for Biomedical Collaborative Research (R01)", we propose studies aiming at the understanding of the genetic architecture of schizophrenia in the Han Chinese population and investigating the shared and ethnic-specific risk factors between the Han Chinese and Caucasian populations. Our aims are: 1. to conduct exome sequencing for 140 nuclear Han Chinese families with multiple affected individuals to discover single nucleotide variations (SNVs) and copy number variations (CNVs) predisposing to the disorder. We plan to use families with both parents (affected or unaffected), 2 affected and 1 unaffected siblings and families with 1 parent, 2 affected and 1 unaffected siblings. The use of families with affected and unaffected siblings allows us to simultaneously discover and characterize transmitted and de novo risk variants. The unaffected siblings in the families are better controls than subjects from the general population, as they can help to distinguish potentially pathological variants from many benign variants observed in the families. 2. To genotype 5,000 cases and 5,000 controls of Han Chinese samples for up to 100 of the most promising risk variants discovered in Aim 1 above to verify their association with SCZ. We will apply a set of sophisticated statistical, bioinformatics and functional filters to select the most promising SNVs. We will focus on those rare variants (including de novo variants) with potential functional consequences and variants occurred at multiple sites in the same genes and biological pathways. 3. To perform comparative analyses using GWAS datasets from both Caucasian and Han Chinese populations to estimate the overlap of genetic risk between the two populations, and to discover and characterize the shared- and ethnic-specific risk genes. We propose to use polygenic analyses to examine the correlation between the PGC and Chinese GWASs to estimate the overlap of risk factors between these populations, and to examine the genetic structure of SCZ in these two ethnic groups.