Systems biology and integrative genomics in neuropsychiatric disorders
Daniel Geschwind, MD, PhD
Professor of Neurology and Psychiatry, University of California, Los Angeles, UCLA
Host: Alex Urban
Advances in genetics and genomics have recently manifest their early promise to expand our understanding of nervous system function in health and disease. Genetic advances have perhaps had their largest impact on neuropsychiatric disorders, such as autism spectrum disorder (ASD), where a large number of genes have already been implicated. At the same time these findings emphasize the extraordinary underlying clinical and genetic heterogeneity, which has led us to conceive of ASD more as “the autisms” than as a singular entity. A major question is thus whether these distinct conditions converge on common molecular pathways. To address this, we reasoned that we could apply systems biology methods previously used to elucidate the structure of the human brain transcriptional network to explore convergence in ASD and other psychiatric disorders. Our findings demonstrate that there is shared, convergent biology involving transcriptional regulation and the development of synaptic function and its modulation by neuro-inflammatory cells in post mortem brain in ASD. We subsequently asked whether ASD risk genes might converge on specific biological processes and brain circuits during early brain development in autism spectrum disorder (ASD). These studies highlight key periods and biological pathways during fetal brain development where autism susceptibility genes are likely to act. We have also used the same systems biology framework to explore convergence and divergence with other neurodevelopmental disorders, and to assess the utility of in vitro model systems for studying human neural development. These studies provide a framework for further functional investigation of disease mechanisms with a goal of accelerating therapeutic development.
 Parikshak NN, Luo, R, Zhang A, Won H, Lowe JK, Chandran V, Horvath SH, Geschwind DH (2013). Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell. 155(5): 1008-21. doi: 10.1016/j.cell.2013.10.031
 Parikshak NN, Swarup V, Belgard TG, Irimia M, Ramaswami G, Gandal MJ, Hartl C, Leppa V, de la Torre Ubieta L, Huang J, Lowe JR, Biencowe BJ, Horvath S, Geschwind DH (2016). Genome-Wide Changes in lncRNA, Splicing, and Regional Gene Expression Patterns in Autism. Nature. 540: 423-427. doi.org/10.1016/j.cell.2016.10.031