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

摘要 双相情感障碍影响着世界上大约1%的人口。我们目前还不了解 双相情感障碍的生物学基础足以设计有效的治疗方法 战略布局双胞胎和收养研究支持遗传病因，我们现在知道这是 在数百个基因中的罕见和常见变体之间分配，每个变体具有一个 小影响。更全面阐明双相情感障碍遗传病因所需的样本量 只有通过大规模的合作努力才能实现混乱。例如，2018年 精神病学基因组学联盟（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。虽然这是 这是理解双相情感障碍遗传学的一个重要里程碑， 只能解释一小部分遗传变异 需要将这一方法推广到其他人口群体，并提供足够的样本 发现与双相情感障碍相关的其他遗传变异。我们建议 从巴基斯坦查明和收集10 000例病例和2 000例对照。我们目前有一个 巴基斯坦正在进行的一项研究（GEN-SCRIP），将收集额外的10，000个对照。我们有 成立了一个由11个中心的巴基斯坦精神病学家组成的联盟。这12,000份样本将 在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)，其将包含约660，000个SNP的骨架，其提供LD覆盖， 对于超过87%的南亚基因组，插补准确度> 0.8。有很强 巴基斯坦的近亲婚姻传统对基因研究有好处， 尤其是遗传特征。我们将分析这些数据中常见的SNP， 单倍型和拷贝数变异（CNVs）。在关联分析中，我们将检查 隐性遗传，以及常见疾病变异的加性模型。我们将 进行纯合性作图以鉴定富含纯合性缺失的区域 (ROH)与对照组相比，这个种群会有不同的联系 不平衡结构，这将有助于缩小基因组间隔含有的 在PGC2 BP GWAS中鉴定的30个基因座处的潜在致病变体。我们将分享这些 通过NIMH Genetics Repository和Genomic， 研究，精神病基因组学联盟和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.