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

3/4 亚洲双相遗传学网络（A-BIG-NET）

• 批准号: 10705721
• 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/10705721
• 关键词: Acceleration; 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; Equity; European; European ancestry; Funding; Gene Frequency; Genetic; Genetic Diseases; Genetic Research; Genetic Variation; Genetic study; Genomics; Genotype; India; International; Joints; Maps; 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; Singapore; Site; South Asian; South Korea; Taiwan; Time; Uncertainty; Variant; Work; 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 risk factor; 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.

项目摘要 双相情感障碍（BP）是一种严重的多因素神经精神疾病，不可能在 公共卫生。 BP的最新大规模遗传研究确定了64个相关的遗传位置，提供 BP发病机理的初始见解。然而，BP的遗传发现落后于其他关键的精神病障碍。这 报道的遗传局部只捕获了总BP遗传责任的一小部分，还有更多变体 在公共和罕见的等位基因频谱中，仍有待发现的频谱。另外，以前 研究的样品是欧洲血统，使人口特定的BP变体发现了不确定性和不确定性 BP遗传发现如何推广到其他人群，加剧医疗保健分布以及这些。 研究很少采用“深”表型或评估相关的环境风险因素。这个建议 汇集了美国台湾，韩国的主要调查员的国际合作， 新加坡，印度和巴基斯坦形成亚洲双极遗传网络（A-BIG-NET），并进行大型 东亚和南亚的BP的规模遗传研究。 A-BIG-NET将产生27,500的BP遗传资源 案例和16,000个对照，具有丰富的表型信息，关键环境压力源的度量和 来自4倍低通的整个基因组测序（4xWG）的遗传数据。这将完成精神分裂症 22,778例遗传学资源和35,362个亚洲血统的控制 该网络将用于跨端比较。研究亚洲的BP遗传学对 世界和美国，作为亚洲宪法的57％，占世界人口的57％，亚裔美国人占6.6％ 美国人口（2140万）。 A-big-net的五个国家占所有亚洲人口的35％。这 该提案的具体目的是：1）招募和深层表型17,500 bp案件，重点是BP-I 最大化同质性，以及来自四个亚洲国家的14,000个控制； 2）对所有招募的所有招聘 样品加上10,000个BP-I病例和2,000例先前研究收集的对照，使用类似程序 巴基斯坦; 3）进行一系列分析，以发现与BP-I的新遗传关联 东亚人群中的频谱，检查BP-I的比较遗传结构 世界主要人群和其他主要神经精神疾病，并进行新的统计精细 - 绘制分析，利用精神疾病跨精神疾病的多种考察基因组多样性和多效性 确定推定的因果变体。 AIM 3还将探索各种BP-I亚型的遗传“有效性”并拟合 具有联合遗传和环境风险因素的模型。该建议将大大增加全球 BP上的仿制数据多样性，这是加速这种疾病中基因并提高基因的重要步骤 全球心理健康公平。