Understanding developmental neurogenomic mechanisms in externalizing disorders - Externalizing disorders are highly heritable psychiatric conditions that typically present in childhood or adolescence and co-occur within individuals. Recent genome-wide association studies have successfully identified hundreds of genetic loci linked to externalizing disorders – many of which are known to be involved in neurodevelopment. Bioinformatic results have bolstered this connection, revealing that the shared genetic architecture of externalizing is enriched for genes that are preferentially expressed during the prenatal period. However, despite these important advances, our understanding of the precise neurodevelopmental mechanisms involved remains limited. Identifying the specific processes that augment the risk for and development of externalizing psychopathology would greatly advance translational knowledge in this domain. In this application, Dr. Travis Mallard will investigate the central hypothesis that externalizing psychopathology is influenced by genes involved in critical neurodevelopmental programs that partially exert their influence via subtle-but-deleterious effects on cortical structure. Specifically, Dr. Mallard will use the Genomic Structural Equation Modeling framework to advance genetic discovery for externalizing disorders (Aim 1), and elucidate the genetic relationships between externalizing and brain structure across development (Aim 2). Using cutting- edge informatic methods, he will then characterize the multidimensional functional profiles of risk genes (Aim 3). These studies will use existing large-scale neurogenomic and clinical datasets and advanced statistical methods that the applicant and his mentorship team have pioneered. Together, these aims will help clarify the complex molecular underpinnings and developmental neurogenomic pathways in externalizing disorders. With his unique background in clinical psychology, complex trait genetics, and human neuroscience, Dr. Mallard is well-qualified to execute the proposed research and training objectives. The four-year training program will foster the applicant’s technical skillset, professional development, and progression toward independence, and the proposed studies will generate vital preliminary data for a future R01 application with therapeutic potential. Dr. Mallard will continue his mentee relationships with Drs. Jordan Smoller and Tian Ge, while receiving training and mentorship in functional genomics and transcriptomics from Dr. Michael Gandal. He has also enlisted several additional renowned clinical scientists to serve on his Expert Advisory Committee: Dr. Danielle Dick, an expert in the genetic etiology of externalizing disorders; Dr. Elliot Tucker-Drob, a statistical genetics and cognitive development expert; and Dr. Armin Raznahan, an expert in developmental neuroscience and genomics. The collaborative research environment is ideal for furthering Dr. Mallard’s goal of becoming an independent clinician-scientist in psychiatric genetics.
