Mapping genes for schizophrenia in a founder population

描述（由申请人提供）：我们建议对南非白人（来自南非的欧洲血统创始人人群）进行多管齐下的人类遗传分析，以确定家族性和非家族性（散发性）精神分裂症的遗传风险因素。我们在上一个资助周期的工作为该疾病的散发性和家族性形式的遗传和生物学基础提供了三个重要的见解：第一，在南非白人人口中，至少有10%的精神分裂症散发病例可以由罕见的新发CNVs解释;第二，精神分裂症家族性病例中的相当一部分可归因于基因区域缺失和重复的罕见遗传性CNVs;第三，部分南非白人精神分裂症家族携带一个或多个位于染色体13 q34的疾病风险基因。我们在该奖项的最后一个资助期的工作代表了第一个以家庭为基础的研究之一，以探索CNV如何有助于已知的精神分裂症遗传模式的重要问题，并决定了该项目下一个资助周期的研究方向。具体而言，我们计划（i）使用家族性和散发性精神分裂症的大群组以及对照群组进行新的高密度全基因组扫描以检测CNV;（ii）采用基于测序的方法来确定受罕见CNV影响的基因中的潜在破坏性突变的总数或从头突变的数量在病例中是否显著高于对照;（iii）以两种互补的方法为基础，进行全面的努力，以探索13 q34精神分裂症易感基因座的遗传结构，最终目标是确定一个或多个常见或罕见的变异，解释在该区域观察到的连锁信号。在独特的阿非利卡人口中进行这项研究的优势怎么强调都不过分。除了是一个种族同质的人口来自少数创始人，家庭结构，家谱研究的潜力和几代人的详细精神病记录的可用性促进了以家庭为基础的精神分裂症研究和高置信度的区别散发和家族性病例。该项目具有巨大的希望，可以揭示精神分裂症的遗传病因，特别是在新建立的技术背景下，可以有效筛选罕见突变。 公共卫生相关性：我们最近的工作为家族性和非家族性精神分裂症的遗传和生物学基础提供了重要的见解，提供了罕见的基因组拷贝数变异（CNV）在这两种疾病的遗传风险中发挥重要作用的证据。我们建议进一步研究精神分裂症中CNVs的全谱特征，并更充分地了解该疾病的遗传结构。我们还建议超越CNV数据，并以全面的方式（使用下一代测序方法）表征位于已确定的疾病风险位点的基因，以获得影响这些基因功能或表达的其他RARE突变。

DESCRIPTION (provided by applicant): We propose to undertake a multi-pronged human genetic analysis on the Afrikaners, a European origin founder population from South Africa, to identify genetic risk factors for both familial and non-familial (sporadic) forms of schizophrenia. Our work during the previous cycle of funding for this grant has provided three important insights in the genetic and biological basis of sporadic and familial forms of the disease: First, that at least 10 percent of sporadic cases of schizophrenia in the Afrikaner population can be accounted for by rare de novo CNVs; second, that a substantial portion of familial cases of schizophrenia can be accounted for by rare inherited CNVs enriched in deletions and duplications of genic regions; and third that a portion of Afrikaner families with schizophrenia carry one or more disease risk genes located at chromosome 13q34. Our work during the last funding period of this award represents one of the first family-based studies to explore the important question of how CNVs contribute to the known inheritance patterns of schizophrenia and dictates the research direction of this project for the next funding cycle. Specifically we plan to (i) undertake a new, high- density genome-wide scan for CNVs using large cohorts of familial and sporadic schizophrenia, as well as control cohorts; (ii) pursue sequencing based approaches to determine whether the total number of potentially damaging mutations or the number of de novo mutations in genes affected by rare CNVs is significantly higher in the cases versus controls; (iii) undertake a comprehensive effort based on two complementary approaches to probe the genetic architecture of the 13q34 schizophrenia susceptibility locus with a final goal to identify one or more common or rare variants accounting for the linkage signal observed in this region. The advantage of doing this research in the unique Afrikaner population cannot be overemphasized. In addition to being an ethnically homogeneous population derived from a small number of founders, the family structure, the potential for genealogical research and the availability of detailed psychiatric records over several generations facilitates family-based studies of schizophrenia and high-confidence distinction of sporadic and familial cases. This project holds tremendous promise to shed light into the genetic etiologies of schizophrenia, especially in the context of newly established technologies that allow efficient screens of rare mutations. PUBLIC HEALTH RELEVANCE: Our recent work has provided important insights into the genetic and biological basis of both familial and non- familial forms of schizophrenia, providing evidence that rare genomic copy number variants (CNVs) play an important role in the genetic risk of both forms of the disease. We propose to pursue further work to characterize the full spectrum of CNVs in schizophrenia and inform the genetic architecture of the disease more fully. We also propose to move beyond the CNV data and characterize in a comprehensive manner (using next generation sequencing approaches) genes located in identified disease risk loci, for additional RARE mutations that affect the function or expression of these genes.