2/2 Neurodevelopmental Genomics: Trajectories of Complex Phenotypes

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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.