2/2 Neurodevelopmental Genomics: Trajectories of Complex Phenotypes

描述（由申请人提供）：精神疾病是在儿童和青少年时期出现的常见疾病，许多人会持续到成年，导致衰弱的后果。为了预防或干预这一途径，确定这些疾病的发病前危险因素和早期表现至关重要。生物和环境风险因素都是精神疾病复杂表型的基础。需要一种综合的方法来阐明影响神经发育轨迹的遗传、表观遗传和环境因素。下一步是将强大的基因组方法应用于表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影响形成复杂行为基础的大脑系统的发展。获得大脑和行为定量表型测量的能力增强，使严谨的研究能够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。费城儿童医院的应用基因组学中心和宾夕法尼亚大学的大脑行为实验室提出的合作利用了一个前所未有的机会：已经有大量的儿童和青少年样本进行了基因分型，这些儿童和青少年已经同意联系他们进行进一步的研究。我们的目标是：1；对1万名基因型儿童和青少年的队列进行表型表征，并评估表明易患重大精神疾病的行为维度。表型维度将包括临床评估，包括对关键特征的分类和维度测量，包括注意力缺陷、焦虑、情绪、精神病倾向和药物滥用；与易受神经发育异常影响的神经系统相关的认知和情绪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：基于形变形态学表征的结构成像，检查白质连通性的扩散加权成像，测量静息脑血流量的动脉自旋标记灌注成像，以及与主要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测量。3. 建立导致精神障碍的神经易感性的基因网络。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谱分析将确定其基因组的DNA图谱，并评估是否有任何基因型状态倾向于特定的甲基化谱。基因组、表观遗传学、影像学和表型数据集的综合分析和测量将进行最佳的基因型-表型关联。生成的数据将按照既定的数据共享指南提供给科学界

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.