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

项目总结 双相情感障碍(BP)是一种严重的多因素神经精神障碍，对 公共卫生。最新的大规模BP遗传研究确定了相关的遗传基因座，为 对BP发病机制的初步认识。然而，BP的基因发现落后于其他关键的精神疾病。这个 已报道的遗传基因座只捕获了BP总遗传易感性的一小部分，还有更多的变异 在常见和罕见的等位基因频率谱上仍有待发现。此外，之前的 研究的样本是欧洲血统，留下了人群特有的BP变异未被发现和不确定性 BP的基因发现如何推广到其他人群，加剧了健康差距，这些研究 很少采用“深层”表型或评估相关的环境风险因素。这项提议带来了 来自美国、台湾、韩国、新加坡、 印度、巴基斯坦将组成亚洲双极遗传网络(A-BIG-NET)并开展大规模遗传 BP在东亚和南亚的研究。A-BIG-Net将产生27,500个病例和16,000个BP遗传资源 具有丰富的表型信息、关键环境应激源的测量和来自4x的遗传数据的对照 低通全基因组测序(4xWGS)。这将补充精神分裂症的遗传资源 22,778个亚洲血统病例和35,362个对照之前由这个网络的领导人收集，将是 可用于交叉无序比较。研究亚洲的BP遗传学对世界和美国都很重要， 由于亚洲占世界人口的57%，亚裔美国人占美国人口的6.6% (2140万)。A-Big-net中的五个国家覆盖了亚洲人口的47%。《公约》的具体目标 建议：1)招募和深入表型17,500个BP病例，重点关注BP-I以最大限度地提高同质性， 来自四个亚洲国家的14,000个对照；2)对所有招募的样本和10,000个BP-I进行4xWGS 在巴基斯坦使用类似程序收集的病例和2,000个对照；以及3)开展 在东部和南部发现与BP-I等位基因谱新的遗传关联的分析范围 亚洲人群，研究BP-I在世界主要人群和 和其他主要的神经精神障碍，并执行一种新的统计精细映射分析，利用 精神障碍的多血统基因组多样性和多效性以确定可能的原因 变种。目标3还将探索不同BP-I亚型和与联合基因相适应的模型的遗传“有效性” 和环境风险因素。这项提议将极大地增加全球遗传数据的多样性。 关于BP，这是加速这种疾病的基因发现和促进全球心理健康公平的重要一步。

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.