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

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，加剧了医疗保健的差异， 研究很少采用“深度”表型分析或评估相关的环境风险因素。这项建议 汇集了来自美国，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），并开展一项大型的 东亚和南亚BP的规模遗传研究。A-BIG-NET将产生27，500个BP遗传资源 病例和16，000名对照，具有丰富的表型信息，关键环境压力源的测量， 4倍低通全基因组测序（4xWGS）。这将补充精神分裂症 之前由亚洲血统领导人收集的22，778例病例和35，362例对照的遗传资源 这个网络将可用于交叉紊乱比较。在亚洲研究BP遗传学对 世界和美国，亚洲占世界人口的57%，亚裔美国人占世界人口的6.6%。 美国人口（2140万）。A-BIG-NET的五个国家覆盖了所有亚洲人口的35%。的 该提案的具体目标是：1）招募并深入表型17，500例BP病例，重点是BP-I， 最大化同质性，以及来自四个亚洲国家的14，000名对照; 2）对所有招募的 样本加上10，000例BP-I病例和2，000例对照，这些病例和对照是由先前的研究使用类似的程序收集的， 巴基斯坦; 3）进行一系列分析，以发现BP-I在等位基因中的新遗传关联。 在东亚和南亚人群中，研究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，并进行了一个新的统计罚款- 利用多祖先基因组多样性和精神疾病多效性的映射分析 来鉴定可能的致病变异目的3还将探索各种BP-I亚型的遗传“有效性”， 遗传和环境风险因素共同作用的模型。这一提议将大大增加世界范围内 BP遗传学数据的多样性，这是加速这种疾病基因发现和进展的重要一步 全球精神卫生公平。

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.