Multimodal Imaging: Genetic and Environmental Effects in Neuropsychiatry

多模态成像：神经精神病学中的遗传和环境影响

• 批准号: 10703942
• 负责人: Karen FAITH Berman
• 金额: $ 152.12万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703942
• 关键词: Acute; Affect; Architecture; Area; Attention deficit hyperactivity disorder; Behavior; Behavioral; Biological; Biological Markers; Biology; Brain; Characteristics; Clinical; Cognitive; Complex; Corpus striatum structure; DNA Sequence; Data; Data Set; Databases; Development; Diffusion Magnetic Resonance Imaging; Disease; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Environment; Functional Magnetic Resonance Imaging; Functional disorder; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Materials; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genome; Genotype; Heritability; Heterogeneity; Human; Individual; Investigation; Life; Link; Magnetic Resonance Spectroscopy; Magnetism; Measurement; Measures; Mediating; Mental disorders; Methodology; Molecular; Molecular Abnormality; Molecular Biology; Multimodal Imaging; Nature; Neuropsychological Tests; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Positron-Emission Tomography; Prefrontal Cortex; Psychoses; Recording of previous events; Regulation; Relaxation; Research; Risk; Risk Factors; Schizophrenia; Severities; Short-Term Memory; Siblings; Sick Role; Structure; Susceptibility Gene; System; Traction; Translating; Twin Studies; Validation; Variant; Work; behavioral phenotyping; biological research; brain behavior; brain tissue; case control; chromosomal location; clinically significant; cognitive ability; cognitive development; cohort; dopamine system; epidemiology study; functional disability; gene environment interaction; genetic architecture; genetic association; genetic testing; genome wide association study; healthy volunteer; imaging genetics; improved; in vivo; multimodality; neural; neurogenetics; neuroimaging; neuropsychiatry; novel; novel therapeutics; obstetrical complication; pre-clinical; protein expression; risk variant; schizophrenia risk; tool; trait; treatment response; urban setting

In order to better understand how the genetic risk for schizophrenia operates at the cognitive, behavioral and neural systems level, our recent work under this project has focused on understanding the biological correlates of both polygenic illness risk and gene-by-environment interactions. Ongoing studies in these areas permit better understanding of heritable, trait-related abnormalities in schizophrenia, of the underlying molecular biology responsible for such abnormalities, and of strategies for resolving some of the illness heterogeneity that makes biological research so challenging. Schizophrenia is highly heritable but, like other psychiatric disorders, its genetic architecture is quite complex. The field has identified numerous genetic markers that are statistically associated with illness in large case-control genome-wide association studies but whose contributions to schizophrenia risk biology remain unclear. Considerable additional work is needed to translate these findings into a better understanding of the molecular pathways leading to system-level dysfunction in schizophrenia. This is exemplified by one of the first genes reaching genome-wide association level significance, ZNF804a, which has continued to be an important locus of schizophrenia risk, but it remains unknown how variation in this gene might confer schizophrenia risk. Following preclinical support for ZNF804a-mediated dopamine receptor regulation, we have employed dopamine receptor PET imaging in a large cohort of healthy volunteers genotyped for the ZNF804a risk locus and identified significant and specific associations between genotype and D2 dopamine receptor availability in the striatum, providing novel evidence that this gene has implications for the dopamine system in the living human brain (Hegarty et al., 2021). Current work employs various strategies beyond single-gene effects, including the use of polygenic scores. These scores, which summarize genetic associations across the genome with a given disorder or trait, are an emerging tool for investigations of broad genetic influences on illness and behavior. For instance, we have shown that in schizophrenia, a profile of polygenic scores separately derived for schizophrenia, ADHD, educational attainment, and cognitive ability predicts distinct trajectories of cognitive development prior to the onset of acute illness. In recent studies examining a set of ancient DNA sequence variants across the genome, we have found that cumulatively, these variants are associated with subtle differences in brain structure and function, including less striatal dopamine synthesis, that may be associated with diminished expression of schizophrenia phenotypes in addition to reduced illness risk and severity (Gregory and Berman, 2022; Gregory et al., 2021). Recent collaborative methodological experimentation has helped develop new data-driven ways of analyzing neuroimaging genetics questions, which will aid discovery of more complex gene-brain relationships despite the multidimensional nature of these data types (Ghosal et al., 2022). In conjunction with genetic factors underlying risk for schizophrenia, environmental influences have been identified as illness risk factors in epidemiological and twin studies, and delineating gene-environment interactions is likely crucial to better understanding the causes of schizophrenia. Recent research has highlighted two environmental variables that show association with schizophrenia: urbanicity and early life complications. For example, we have demonstrated that whether an individual was raised in an urban environment significantly modifies effects of dopamine-related genes on how the prefrontal cortex responds to working memory demands. We have further replicated this finding in two additional datasets and posit that urban upbringing may alter brain function in a way that meaningfully intersects with dopaminergic neurogenetic mechanisms. Other work suggests that the predictive strength of most strongly associated chromosomal location from the recent schizophrenia genome-wide association study is greatly amplified when there is a history of clinically significant obstetrical complications. These data suggest that traditional univariate approaches must be buttressed by gene-by-environment experimentation to more fully elaborate genetic risk architecture in schizophrenia.

为了更好地了解精神分裂症的遗传风险是如何在认知、行为和神经系统水平上运行的，我们最近在该项目下的工作集中在了解多基因疾病风险和基因与环境相互作用的生物学相关性上。这些领域正在进行的研究使人们能够更好地了解精神分裂症中可遗传的、与特征相关的异常，了解导致这种异常的潜在分子生物学，以及解决使生物学研究如此具有挑战性的一些疾病异质性的策略。 精神分裂症是高度可遗传的，但像其他精神疾病一样，它的基因结构相当复杂。在大型病例对照全基因组关联研究中，该领域已经确定了许多与疾病在统计上相关的遗传标记，但其对精神分裂症风险生物学的贡献尚不清楚。还需要大量的额外工作来将这些发现转化为更好地理解导致精神分裂症系统水平功能障碍的分子途径。最早达到全基因组关联水平的基因之一ZNF804a就是一个例证，它一直是精神分裂症风险的重要基因座，但尚不清楚该基因的变异如何可能赋予精神分裂症风险。在临床前支持ZNF804a介导的多巴胺受体调节之后，我们在一大群健康志愿者中使用了ZNF804a风险基因分型的多巴胺受体PET成像，发现了纹状体中D2多巴胺受体可获得性和基因之间的显著和特定的关联，提供了新的证据，表明该基因对活体人脑中的多巴胺系统有影响(Hegarty等，2021)。 目前的工作采用了各种策略，超越了单基因效应，包括使用多基因评分。这些分数总结了整个基因组与给定疾病或特征的遗传关联，是研究广泛的基因对疾病和行为影响的新兴工具。例如，我们已经证明，在精神分裂症中，分别为精神分裂症、ADHD、教育程度和认知能力得出的多基因分数分布可以预测急性疾病发病前认知发展的不同轨迹。在最近对基因组中一组古老的DNA序列变异的研究中，我们发现这些变异累积起来与大脑结构和功能的细微差异有关，包括纹状体多巴胺合成减少，这可能与精神分裂症表型表达减少有关，此外还降低了疾病风险和严重程度(Gregory和Berman，2022；Gregory等人，2021)。最近的协作方法论实验帮助开发了分析神经成像遗传学问题的新的数据驱动的方法，这将有助于发现更复杂的基因-大脑关系，尽管这些数据类型具有多维性质(Ghosal等人，2022)。 在流行病学和双生子研究中，环境影响与精神分裂症风险的遗传因素一起被确定为疾病风险因素，描绘基因与环境的相互作用可能对于更好地理解精神分裂症的病因至关重要。最近的研究强调了两个与精神分裂症有关的环境变量：都市性和早期生活并发症。例如，我们已经证明，一个人是否在城市环境中长大，会显著改变多巴胺相关基因对前额叶皮质对工作记忆需求的反应。我们在另外两个数据集中进一步重复了这一发现，并假设城市教育可能会以一种与多巴胺能神经遗传机制有意义地交叉的方式改变大脑功能。其他工作表明，当有临床上重大产科并发症的历史时，最近的精神分裂症全基因组关联研究中最强关联的染色体位置的预测能力被大大放大。这些数据表明，传统的单变量方法必须得到逐个环境的基因实验的支持，以更充分地阐述精神分裂症的遗传风险结构。

项目成果

WWC1 genotype modulates age-related decline in episodic memory function across the adult life span.

• DOI: 10.1016/j.biopsych.2013.09.036
• 发表时间: 2014-05-01
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Muse J;Emery M;Sambataro F;Lemaitre H;Tan HY;Chen Q;Kolachana BS;Das S;Callicott JH;Weinberger DR;Mattay VS
• 通讯作者: Mattay VS

Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans.

• DOI: 10.1038/mp.2013.133
• 发表时间: 2014-03
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Papaleo F;Burdick MC;Callicott JH;Weinberger DR
• 通讯作者: Weinberger DR