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

描述(申请人提供)：神经发育疾病，如精神分裂症，是一种常见的、复杂的遗传疾病，影响较高的认知功能，给个人和社会带来沉重的负担。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，然而，关于哪些基因与不同环境相互作用影响已知的与遗传性疾病风险相关的高级认知脑过程，人们知之甚少。因此，美国和中国合作的这项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截然不同程度的城乡儿童高级大脑功能的影响，以及在其祖先多样性相对有限的人群中，这些影响可能如何影响与疾病相关的基因控制的高级皮质功能。在目标1中，我们将使用功能磁共振，在一项双胞胎研究中确定与精神分裂症遗传风险相关的前额叶-纹状体-海马体回路中间表型，并补充来自患者和兄弟姐妹的神经成像数据。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大脑表型和目标1中对环境敏感的脑表型来检查特定的基因-环境交互作用。这些关联将在现有的全基因组关联数据集中以及在人类整个生命周期中的前额叶和死后脑表达谱方面进行进一步的询问。在研究结束时，我们将确定童年时期农村或城市成长对与精神分裂症遗传风险有关的高级大脑功能的影响，以及推测遗传对这些环境大脑影响的影响。这将增加关于儿童环境的可改变方面和潜在的新的遗传病机制如何偏向于精神分裂症的风险或复原力的知识。

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.