Effects of genes and childhood environment on brain mechanisms of schizophrenia r

描述（由申请人提供）：精神分裂症等神经发育疾病是常见的复杂遗传性疾病，影响高级认知功能，对个人和社会造成沉重负担。发育环境也被证明会增加疾病风险，例如宫内感染，营养缺乏和城市生活，但是，对于哪些基因与不同环境相互作用以影响已知与疾病遗传风险相关的高级认知脑过程知之甚少。因此，这项中美合作研究的目标是利用中国独特的自然主义研究机会，有力地研究中国独特的经济发展对农村和城市儿童不同程度的高级大脑功能的影响，以及这些可能如何影响与疾病相关的遗传控制的高级皮质功能，在其祖先多样性相对有限的人口中。在目标1中，我们将在一项双胞胎研究中使用功能性MRI来定义与精神分裂症遗传风险相关的前额叶-纹状体-海马回路中间表型，并辅以患者和兄弟姐妹的神经影像学数据。我们还将确定不同程度的童年城市或农村环境对成年个体中这些中间表型的影响，控制智商，社会经济地位和遗传异质性。在目标2中，使用候选基因和全基因组策略，我们将基于与精神分裂症遗传风险相关的脑表型和对目标1中环境敏感的脑表型来检查特定的基因-环境相互作用。这些关联将在现有的全基因组关联数据集中进一步询问，并在整个人类寿命期间的前额叶和海马死后脑表达谱方面。在研究的最后，我们将确定童年农村或城市教养对精神分裂症遗传风险所涉及的高级脑功能的影响，以及对这些环境脑效应的推定遗传影响。这将增强有关儿童环境的可改变方面以及潜在的新遗传疾病机制如何偏向精神分裂症风险或恢复力的知识。

DESCRIPTION (provided by applicant): Neurodevelopmental diseases like schizophrenia are common, complex genetic disorders that affect higher cognitive function, and exact a high burden on individuals and society. The developmental environment has also been shown to increase disease risk, for example intrauterine infection, nutritional deprivation and urban living However, little is known about which genes interact with different environments to influence higher cognitive brain process known to be associated with heritable risk for disease. Thus, the goal of this collaborative US-China study is to leverage China's exceptional naturalistic research opportunities to powerfully examine the effects on higher brain functions of starkly different degrees of rural and urban childhoods resulting from China's unique economic development, and how these may influence genetically controlled higher-cortical functions linked with disease, within its population of relatively limited ancestral diversity. In Aim 1, we will define, using functional MRI, prefrontal- striatal-hippocampal circuit intermediate phenotypes associated with heritable risk for schizophrenia in a twin study, supplemented by neuroimaging data from patients and siblings. We will also define the effects of differing degrees of childhood urban or rural environments on these intermediate phenotypes in adult individuals, controlling for IQ, socioeconomic status and genetic heterogeneity. In Aim 2, using a candidate gene and genome-wide strategy, we will examine specific gene-environment interactions based on the brain phenotypes associated with heritable risk for schizophrenia and sensitive to the environment in Aim 1. These associations will be further interrogated in available genome-wide association datasets, and in terms of prefrontal and hippocampal postmortem brain expression profiles across the human lifespan. At the end of the study, we will have defined the influence of childhood rural or urban upbringing on higher brain functions implicated in heritable risk of schizophrenia, and putative genetic influences on these environmental brain effects. This will enhance knowledge about how modifiable aspects of the childhood environment and potentially novel genetic disease mechanisms biases towards risk or resilience for schizophrenia.