1/4 Asian Bipolar Genetics Network (A-BIG-NET)

1/4 亚洲双相遗传学网络（A-BIG-NET）

• 批准号: 10501841
• 负责人: Hailiang Huang
• 金额: $ 178.83万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501841
• 关键词: Adopted; Adult; Alleles; Asia; Asian; Asian Americans; Asian ancestry; Asian population; Bipolar Disorder; Clinical; Collaborations; Complement; Consensus; Country; DNA; Data; Disease; East Asian; Environmental Risk Factor; European; Funding; Gene Frequency; Genetic; Genetic Diseases; Genetic Research; Genetic Risk; Genetic Variation; Genetic study; Genomics; Genotype; India; Institutes; International; Joints; Life; Measures; Mental Health; Mental disorders; Modeling; Molecular; Molecular Genetics; National Institute of Mental Health; Nature; Outcome; Pakistan; Pathogenesis; Phenotype; Play; Population; Prevalence; Procedures; Process; Production; Protocols documentation; Public Health; Publications; Quality Control; Records; Reduce health disparities; Reporting; Research; Research Personnel; Research Project Grants; Resources; Role; Sampling; Sampling Studies; Schizophrenia; Ships; Singapore; Site; South Asian; South Korea; Taiwan; Time; Uncertainty; Variant; Work; base; causal variant; cohort; comparative; data archive; data collection site; disorder subtype; environmental stressor; experience; field study; gene discovery; genetic architecture; genetic association; genetic resource; genetic signature; genetic variant; genome sequencing; genomic data; genomic locus; health disparity; health equity; insight; neuropsychiatric disorder; novel; phenotypic data; pleiotropism; polygenic risk score; psychiatric genomics; psychogenetics; rare variant; recruit; severe psychiatric disorder; web portal; whole genome

PROJECT SUMMARY Bipolar disorder (BP) is a severe multifactorial neuropsychiatric disorder that imposes a significant burden on public health. The most recent large-scale genetic study of BP identified 64 associated genetic loci, providing initial insights in BP pathogenesis. Yet, genetic discovery in BP lags behind other key psychiatric disorders. The reported genetic loci only capture a small proportion of the total BP genetic liability, with many more variants across the common and rare allele frequency spectrum remaining to be discovered. In addition, the previous studied samples were of European ancestry, leaving population specific BP variants uncovered and uncertainty in how the BP genetic findings generalize to other populations, exacerbating health disparities, and these studies rarely employed “deep” phenotyping or assessed relevant environmental risk factors. This proposal brings together an international collaboration of leading investigators from the U.S., Taiwan, South Korea, Singapore, India, and Pakistan to form the Asian Bipolar Genetics Network (A-BIG-NET) and carry out a large-scale genetic study of BP in East and South Asia. A-BIG-NET will generate a BP genetic resource of 27,500 cases and 16,000 controls with rich phenotypic information, measures of key environmental stressors and genetic data from 4x low-pass whole genome sequencing (4xWGS). This will complement a schizophrenia genetics resource of 22,778 cases and 35,362 controls of Asian ancestry previously assembled by leaders of this network that will be available for cross-disorder comparisons. Studying BP genetics in Asia is important to the world and the U.S., as Asia constitutes 57% of the world population, and Asian American comprises 6.6% of the U.S. population (21.4 million). The five countries in A-BIG-NET cover 47% of all Asian populations. The specific aims of the proposal are to: 1) recruit and deeply phenotype 17,500 BP cases, with a focus on BP-I to maximize homogeneity, and 14,000 controls from four Asian countries; 2) carry out 4xWGS on all recruited samples plus 10,000 BP-I cases and 2,000 controls collected by a previous study using similar procedures in Pakistan; and 3) carry out a range of analyses to discover new genetic associations with BP-I across the allelic spectrum in East and South Asian populations, examine the comparative genetic architecture of BP-I across major world populations and with other major neuropsychiatric disorders, and perform a novel statistical fine-mapping analysis that leverages the multi-ancestry genomic diversity and pleiotropy across psychiatric disorders to identify putative causal variants. Aim 3 will also explore the genetic “validity” of various BP-I subtypes and fit models with joint genetic and environmental risk factors. This proposal will dramatically increase the worldwide diversity of genetics data on BP, an important step to accelerate gene discovery in this disorder and advance global mental health equity.

项目摘要 双相情感障碍（BP）是一种严重的多因素神经精神障碍， 公共卫生最近的大规模BP遗传研究确定了64个相关的遗传位点， 对BP发病机制的初步认识。然而，BP的遗传发现落后于其他关键的精神疾病。的 报告的遗传位点仅捕获总BP遗传易感性的一小部分，具有更多的变体 常见和罕见的等位基因频率谱仍有待发现。加上此前 研究的样本是欧洲血统，留下人口特定的BP变异未被发现， BP基因研究结果如何推广到其他人群，加剧了健康差异，这些研究 很少采用“深度”表型分析或评估相关的环境风险因素。这项提议带来了 来自美国的主要调查人员的国际合作，台湾、韩国、新加坡、 印度和巴基斯坦组成亚洲双极遗传学网络（A-BIG-NET）， 东亚和南亚的BP研究。A-BIG-NET将产生27,500例和16000例的BP遗传资源 对照组具有丰富的表型信息、关键环境压力源的测量和来自4x 低通全基因组测序（4xWGS）。这将补充精神分裂症遗传资源， 22，778例和35，362例亚洲血统的控制，此前由该网络的领导人收集， 可用于交叉紊乱比较。在亚洲研究BP遗传学对世界和美国都很重要， 亚洲占世界人口的57%，亚裔美国人占美国人口的6.6%。 (21.4百万）。A-BIG-NET的五个国家覆盖了所有亚洲人口的47%。该委员会的具体目标 建议是：1）招募和深入表型17,500例BP病例，重点是BP-I，以最大限度地提高同质性， 和来自四个亚洲国家的14，000个对照; 2）对所有招募的样本加上10，000个BP-I进行4xWGS 病例和2,000例对照，这些病例和2,000例对照是以前在巴基斯坦使用类似程序进行的研究收集的;以及3）进行一项 一系列的分析，以发现新的遗传关联与BP-I跨越等位基因谱在东部和南部 亚洲人群，检查BP-I在世界主要人群中的比较遗传结构， 与其他主要的神经精神疾病，并进行一种新的统计精细映射分析，利用 精神疾病的多祖先基因组多样性和多效性，以确定推定的因果关系 变体。目的3还将探索各种BP-I亚型的遗传“有效性”，并拟合具有联合遗传学特征的模型。 环境风险因素。这一提议将大大增加全球遗传学数据的多样性 这是加速发现这种疾病的基因和促进全球精神卫生公平的重要一步。