2/2 Neurodevelopmental Genomics: Trajectories of Complex Phenotypes

描述（由申请人提供）：精神疾病是儿童和青少年时期出现的常见疾病，许多持续到成年，具有使人衰弱的后果。为了预防或干预这一途径，必须确定发病前的风险因素和这些疾病的早期表现。生物和环境风险因素都是精神疾病表现出的复杂表型的基础。需要一个综合的方法来阐明遗传，表观遗传和环境因素，形成神经发育轨迹。下一步是将强大的基因组方法应用于表现型特征良好的儿童和青少年。将疾病表型和中间变量联系起来，调节遗传易感个体的疾病表现，将有助于阐明这些因素如何有助于塑造复杂行为背后的大脑系统的发展。获得大脑和行为的定量表型测量的能力的提高使得能够进行严格的研究，从而可以将分子生物学与疾病现象学联系起来。可靠的进展需要大量的表型和基因组特征样本。 费城儿童医院应用基因组学中心和宾夕法尼亚大学脑行为实验室之间的拟议合作利用了一个前所未有的机会：一个已经基因分型的儿童和青少年大样本，他们同意被联系进行进一步研究。我们的目标是：1.对10，000名基因分型儿童和青少年进行表型表征，并评估表明易患主要精神疾病的行为维度。表型维度将包括临床评估，包括注意力缺陷、焦虑、情绪、精神病倾向和药物滥用等关键特征的分类和维度测量;与易受神经发育畸变影响的神经系统相关的认知和情感处理的神经行为测量。2.在随机子样本中进行神经成像，以建立行为表型轨迹的神经基质。神经成像方式将包括：基于变形的形态学表征的结构成像、检查白色物质连通性的扩散加权成像、测量静息脑血流的动脉自旋标记灌注成像，以及用于与重大精神疾病有关的神经回路的神经行为探针的脑激活的血氧水平依赖性测量。3.建立导致精神障碍的神经元脆弱性的基因网络。对接受神经影像学研究的受试者子集进行全基因组甲基化分析，将确定其基因组的DNA图谱，并评估任何基因型状态是否易患特定的甲基化谱。然后将对基因组、表观遗传、成像和表型数据集和测量进行综合分析，以获得最佳的基因型-表型关联。所产生的数据将按照既定的数据共享准则提供给科学界。）甲基化 公共卫生相关性：基因组学的进步正在彻底改变医学，其发现有助于阐明机制和设计新的治疗方法。为了让精神疾病从基因组学中受益，需要在大规模的前瞻性样本中将行为与大脑功能联系起来。我们提出了10，000名基因型儿童和青少年的表型特征-临床，神经认知，情感，以及子样本中的神经成像-创建一个具有里程碑意义的数据集，以推动对发育性神经精神障碍的理解和治疗。

DESCRIPTION (provided by applicant): Mental illnesses are common disorders that emerge during childhood and adolescence and many persisting into adulthood, with debilitating consequences. To prevent or intervene in this pathway it is essential to identify premorbid risk factors and early manifestations of these conditions. Both biologic and environmental risk factors underlie the complex phenotypes manifested in mental illnesses. An integrative approach is required to elucidate genetic, epigenetic, and environmental factors, which shape neurodevelopmental trajectories. The next step is to apply powerful genomic methods in phenotypically well-characterized children and adolescents. Linking disease phenotypes and intermediate variables, modulating disease manifestations in genetically susceptible individuals, will help articulate how these factors contribute to shaping the development of brain systems that underlie complex behavior. The increased ability to obtain quantitative phenotypic measures of brain and behavior enables rigorous research that can bridge molecular biology with the phenomenology of disease. Large phenotypically and genomically characterized samples are required for reliable progress. The proposed collaboration between the Center for Applied Genomics at Children's Hospital of Philadelphia and the Brain Behavior Laboratory at the University of Pennsylvania capitalizes on an unprecedented opportunity: an already genotyped large sample of children and adolescents who have consented to being contacted for further research. Our aims are: 1. Characterize phenotypically a cohort of 10,000 genotyped children and adolescents and assess behavioral dimensions indicating vulnerability to major mental illnesses. The phenotypic dimensions will include clinical assessment with categorical and dimensional measures of key features including attention deficit, anxiety, mood, psychosis proneness and substance abuse; Neurobehavioral measures of cognitive and emotion processing related to neural systems vulnerable to neurodevelopmental aberrations. 2. Perform neuroimaging in a random subsample to establish neural substrates of behavioral phenotypic trajectories. Neuroimaging modalities will include: structural imaging with deformation based morphometric characterization, diffusion weighted imaging examining white matter connectivity, arterial spin labeled perfusion imaging measuring resting cerebral blood flow, and blood oxygenation level dependent measures of cerebral activation for neurobehavioral probes of neural circuitries implicated in major mental illnesses. 3. Establish gene networks underlying neuronal vulnerability leading to mental disorders. Genome-wide methylation profiling on the subset of subjects who undergo neuroimaging studies will determine the DNA landscape of their genomes and assess whether any genotype states predispose to specific methylation profiles. Integrative analyses of the genomic, epigenetic, imaging and phenotypic datasets and measures will then be conducted for optimal genotype-phenotype association. Data generated will be available to the scientific community following established data sharing guidelines. ) methylation PUBLIC HEALTH RELEVANCE: Advances in genomics are revolutionizing medicine with discoveries that help elucidate mechanisms and design novel treatments. For mental illnesses to benefit from genomics, data are needed linking behavior to brain function in large prospective samples. We propose phenotypic characterization of 10,000 genotyped children and adolescents - clinical, neurocognition, affect and, in a subsample, neuroimaging - creating a landmark dataset to propel understanding and treatment of developmental neuropsychiatric disorders.