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

GEN-BLIP 研究（巴基斯坦双相情感障碍的遗传学）

基本信息

批准号：
10034810
负责人：
JAMES A KNOWLES
金额：
$ 63.7万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-07 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10034810
关键词：
Adoption Affect Biological Bipolar Disorder Caucasians Cells Characteristics Cohort Studies Collection Communities Consanguinity Consent Copy Number Polymorphism DNA DSM-IV Data Data Analyses Deposition Disease Ethnic Origin European Family Family Sizes Follow-Up Studies Funding Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic study Genome Genomics Genotype Goals Haplotypes Human Genetics Human Inbreeding Individual Inherited Institutes Intellectual functioning disability Intervention Interview Interviewer Linkage Disequilibrium Manic Disorder Mental disorders Modeling National Institute of Mental Health Pakistan Patients Phenotype Population Population Group Proteins Psychiatrist Psychiatry Recording of previous events Research Risk Running Sample Size Sampling Schizoaffective Disorders Schizophrenia Ships Site South Asian Structure Target Populations Testing Training Transcript Twin Multiple Birth Variant Vertebral column causal variant cohort cost data sharing database of Genotypes and Phenotypes design effective therapy family genetics genetic variant genome wide association study genomic locus neural circuit phenotypic data population stratification psychiatric genomics psychogenetics public repository repository screening trait treatment strategy working group

项目摘要

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.

抽象的躁郁症影响了大约1％的世界人口。我们目前不了解双相情感障碍的生物基础足以设计有效的治疗策略。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的稀有变体和常见变体之间分区，每个变体都有一个小效果。更完全阐明双极的遗传病因所需的样本量疾病只能通过大规模的协作努力来实现。例如，2018年精神病基因组学联盟（PGC）躁郁症全基因组关联研究（GWAS）使用带有欧洲血统的样品发现了30个重要的基因座。虽然是理解躁郁症的遗传学的重要里程碑，共同为这些基因座仅解释一小部分遗传方差。需要将这种方法扩展到其他人群群体，具有足够的样本量发现与躁郁症相关的其他遗传变异。我们建议从巴基斯坦确定并收集10,000例和2,000例对照。我们目前有一个巴基斯坦正在进行的研究（Gen-Scrip）将收集另外10,000个对照。我们有在11个中心组成了巴基斯坦精神科医生的财团。 12,000个样本将是 Illumina全球筛选阵列在斯坦利精神病研究中心进行基因分型（GSA），其中将包含约660,000个SNP的骨干，提供LD覆盖范围和超过87％的南亚基因组的插补精度> 0.8。有一个强大的巴基斯坦的近亲婚姻传统，这对于遗传研究具有优势，尤其是隐性遗传特征。我们将分析这些数据的常见SNP，单倍型和复制号变化（CNV）。在关联分析中，我们将研究隐性继承，除了疾病的常见变体的加性模型。我们将执行纯合性映射以识别富含纯合性运行的区域（ROH）在情况下，与对照组相比。这个人群将有不同的联系不平衡结构将有助于缩小包含含义的基因组间隔 PGC2 BP GWAS中鉴定出的30个基因座的潜在因果变体。我们将分享这些通过NIMH遗传学存储库和基因组与更广泛的科学界的数据数据研究，精神病基因组学联盟和DBGAP。