Genetic Influences on Infant Brain Development: Understanding the Developmental Origins of Mental Illness

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PROJECT SUMMARY Despite decades of research psychiatric disorders continue to be a leading source of disability in the United States and across the world. A key challenge for those seeking to develop new therapeutics is that by the time clinical symptoms of mental illness are recognized, much of the underlying pathologic brain development has already occurred and may be irreversible. Consequently, our best hope of significantly impacting care and out- comes in these devastating disorders is via prevention and very early intervention, which our proposed research will help enable, by integrating genomics with longitudinal, pediatric imaging data and behavioral phenotyping to better understand the developmental origins of mental illness. Our central hypothesis is that genetic variants associated with psychiatric disorders increase risk by influencing early neurodevelopment and the establishment of brain circuitry. This hypothesis is supported by several large-scale studies which performed functional genomic characterization of loci that confer risk for multiple psychiatric disorders and revealed enrichment for genes reg- ulating nervous system development, as well as innovative studies by our group in which we 1) discovered variation in putative risk genes for Alzheimer's disease and mental illness are associated with brain changes at birth, and 2) uncovered new genes and variants implicated in brain development, using GWAS. These findings were based on cross-sectional data, collected close to birth. To more fully understand how DNA variants influ- ence brain development in infancy and early childhood, and potential implications for future research and clinical care, large, longitudinal studies are needed. Our proposed study will meet this need, and test our central hypoth- esis by 1) harmonizing a rich array of genetic, neuroimaging, and behavioral data across 19 large and diverse infant and pediatric cohorts from the U.S., Europe, South Africa, and Asia (N=6809, most with two or more longitudinal brain scans and developmentally appropriate measures of impulsivity, anxiety, and aggressive be- havior); 2) determining how common genetic variants, including those associated with mental illness, influence developmental imaging phenotypes (DIPs) derived from structural MRI, diffusion tensor imaging (DTI), and rest- ing state fMRI; and 3) identifying relationships between genetically-influenced DIPs and clinically-salient behav- iors using powerful multivariate analysis methods. Our research team includes world thought-leaders in infant imaging, genomic approaches to understanding complex traits, and behavioral assessment of infants and young children, all working together as the Organization for Imaging Genomics of Infancy (ORIGIN). We are also part of the ENIGMA consortium and will leverage the intellectual resources of this highly successful group. The ap- plication is innovative in its focus on infancy and early childhood, longitudinal design, and in leveraging a unique global alliance of researchers to create the largest-ever imaging genomics dataset focused on infancy and early childhood. The proposed research will have a positive impact because it will enhance our fundamental under- standing of how genetic factors influence brain development and lay the groundwork for a promising new line of research focused on early intervention in individuals at high risk for developing a psychiatric disorder.