The GEN-BLIP Study (GENetics of BipoLar Disorder In Pakistan)

摘要 双相情感障碍影响了大约1%的世界人口。我们目前还不清楚 双相情感障碍的生物学基础足以设计出有效的治疗方法 战略。双胞胎和领养研究支持遗传病因学，我们现在知道这是 在数百个基因中既有罕见的变异也有常见的变异，每个变异有一个 效果不大。更全面地阐明双相情感障碍的遗传病因所需的样本量 混乱只能通过大规模的合作努力才能实现。例如，2018年 精神科基因组学联盟(PGC)双相情感障碍全基因组关联研究 (Gwas)使用具有欧洲血统的样本发现了30个重要的基因座。尽管这是 理解双相情感障碍遗传学的一个重要里程碑，统称为这些基因座 只能解释一小部分遗传变异。 需要将这一方法推广到具有足够样本量的其他人口群体。 发现与双相情感障碍相关的其他遗传变异。我们建议 查明并收集来自巴基斯坦的10,000个病例和2,000个控制措施。我们目前有一个 在巴基斯坦正在进行的研究(Gen-SCRIPP)将收集额外的10,000个对照。我们有 在11个中心组成了一个巴基斯坦精神病学家联盟。这12,000个样本将是 斯坦利精神病学研究中心使用Illumina全球筛查阵列进行基因分型 (GSA)，它将包含一个约660,000个SNPs的主干，提供LD覆盖和 对南亚基因组87%以上的推算准确率为&gt；0.8。有一种强烈的 巴基斯坦血缘婚姻的传统对基因研究具有优势， 尤其是关于隐性遗传的特征。我们将分析这些数据中常见的SNP， 单倍型和拷贝数变异(CNV)。在关联分析中，我们将检查 隐性遗传，以及疾病常见变异的加性模型。我们会 执行纯合性图谱以识别为纯合性运行而丰富的区域 (ROH)在病例中，与对照相比。这一群体将有不同的联系 不平衡结构，这将有助于缩小包含 在PGC2碱基序列中发现的30个基因座上存在潜在的致病变异。我们将分享这些 通过NIMH基因库和基因组与更广泛的科学界共享数据 研究，精神病学基因组联盟和DBGaP。

ABSTRACT Bipolar Disorder affects about 1 percent of the world population. We do not currently understand the biological underpinnings of Bipolar Disorder well enough to design effective treatment strategies. Twin and adoption studies support a genetic etiology and we now know this is partitioned between both rare and common variants in hundreds of genes, each variant having a small effect. The sample size required to more fully elucidate the genetic etiology of Bipolar Disorder can only be achieved through large scale collaborative efforts. For instance, the 2018 Psychiatric Genomics Consortium (PGC) Bipolar Disorder Genome-Wide Association Study (GWAS) discovered 30 significant loci using samples with European ancestry. Although this is an important milestone in understanding the genetics of Bipolar Disorder, collectively these loci only explain a small proportion of the genetic variance. Expansion of this approach to other population groups, with adequate sample size, is required to discovery of additional genetic variants associated with Bipolar Disorder. We propose to ascertain and collect 10,000 cases and 2,000 controls from Pakistan. We currently have an ongoing study in Pakistan (GEN-SCRIP) that will collect an additional 10,000 controls. We have formed a consortium of Pakistani psychiatrists at 11 centers. The 12,000 samples will be genotyped at Stanley Center for Psychiatric Research with Illumina Global Screening Array (GSA), which will contain a backbone of ~660,000 SNPs, which provides LD coverage and imputation accuracy of >0.8, for over 87% of the South Asian genome. There is a strong tradition of consanguineous marriages in Pakistan which has an advantage for genetic studies, especially of recessively inherited traits. We will analyze these data for common SNPs, haplotypes, and copy number variations (CNVs). In association analysis we will examine for recessive inheritance, in addition to additive models of common variants to disease. We will perform a homozygosity mapping to identify regions that are enriched for Runs of Homozygosity (ROH) in cases, as compared to controls. This population will have a different linkage disequilibrium structure which will help to narrow down the genomic intervals containing the potential causative variants at the 30 loci identified in the PGC2 BP GWAS. We will share these data with broader scientific community via the NIMH Genetics Repository and Genomic Research, the Psychiatric Genomics Consortium and dbGaP.