3/4 Asian Bipolar Genetics Network (A-BIG-NET)

3/4 亚洲双相情感网络（A-BIG-NET）

• 批准号: 10502275
• 负责人: Peter P. Zandi
• 金额: $ 20.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10502275
• 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 care disparity; 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 healthcare 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 35% 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.

项目概要 双相情感障碍（BP）是一种严重的多因素神经精神疾病，给患者带来巨大负担 最新的 BP 大规模基因研究确定了 64 个相关基因位点，提供了 然而，对 BP 发病机制的初步认识落后于其他关键精神疾病。 报道的遗传位点仅占 BP 遗传责任的一小部分，还有更多的变异 此外，还有待发现的常见和罕见等位基因频谱。 研究样本具有欧洲血统，导致人群特定的血压变异未被发现并存在不确定性 BP 基因发现如何推广到其他人群，检查医疗保健差异，以及这些 研究很少采用“深度”表型分析或评估相关的环境风险因素。 汇集了来自美国、台湾、韩国、 新加坡、印度和巴基斯坦组建亚洲双极遗传学网络（A-BIG-NET）并开展大规模 东亚和南亚的 BP 大规模遗传研究将产生 27,500 个 BP 遗传资源。 病例和 16,000 个对照，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) 的遗传数据这将补充精神分裂症。 22,778 例亚洲血统病例和 35,362 例对照的遗传资源，此前由以下国家的领导人收集 这个可用于跨疾病比较的网络对于研究亚洲的 BP 遗传学非常重要。 世界和美国，亚洲人口占世界人口的 57%，亚裔美国人占世界人口的 6.6% 美国人口（2140 万）。A-BIG-NET 中的五个国家覆盖了亚洲总人口的 35%。 该提案的具体目标是：1) 招募 17,500 个 BP 病例并对其进行深入表型分析，重点是 BP-I 最大限度地提高同质性，并对来自四个亚洲国家的 14,000 名对照进行 2) 对所有招募的人员进行 4xWGS； 样本加上先前研究使用类似程序收集的 10,000 个 BP-I 病例和 2,000 个对照 巴基斯坦；3) 进行一系列分析以发现等位基因中与 BP-I 的新遗传关联 东亚和南亚人群的谱，检查 BP-I 的比较遗传结构 世界主要人口和其他主要神经精神疾病，并进行了一项新颖的统计精细- 利用多祖先基因组多样性和跨精神疾病的多效性进行图谱分析 目标 3 还将探索各种 BP-I 亚型和拟合的遗传“有效性”。 该提案将极大地增加全球范围内的联合遗传和环境风险因素的模型。 BP 遗传学数据的多样性，是加速这种疾病基因发现和推进的重要一步 全球心理健康公平。