Genetic and genomic investigations have yielded important findings as to the genetic contributions to majorpsychiatric illnesses, illustrating significant etiological heterogeneity, as well as cross-disorder overlap. It hasalso become clear that understanding how this genetic variation leads to alterations in brain development andfunction that underlies psychiatric disease pathophysiology will be greatly advanced by a roadmap of thetranscriptomic and epigenetic landscape of the human cerebral cortex across key developmental windows.Here, we propose, via a highly collaborative group of investigators, each with distinct areas of expertise andresearch focus, to create a scaffold of genomic data for understanding ASD pathophysiology, and psychiatricdisorders more broadly. The work proposed here represents an ambitious multi-PI project (Yale, UCLA, andUCSF) that brings together three principal investigators and collaborators with strong publication records andexpertise in all approaches necessary to perform this work using state-of-the-art and novel methodologies. Wewill perform time-, region-, and cell type-specific molecular profiling of control and ASD brains (Aim 1),including RNA-seq based transcriptomics, identifying cis-regulatory elements via ChIP-seq, and use Hi-C todetermine the 3D chromatin architecture and physical relationships that underlie transcriptional regulation inthree major regions implicated in neuropsychiatric disease (frontal and temporal cortex and striatum) acrossfive major epochs representing disease-relevant stages in human brain development. This will includecomplementary genomic analyses in controls and matched post mortem ASD brain to identify geneticmechanisms underlying processes altered in ASD brain. We will address cellular heterogeneity viafluorescence-activated nuclear sorting (FANS) so as to profile neurons and non-neural cells separately, whichwill complement the whole tissue analyses. We will analyze and integrate these datasets to identify regional,developmental, and ASD-related processes to gain insight into underlying mechanisms, harmonizing thesemulti-omic data with other psychENCODE studies, as well as other large scale data sets, such as BrainSpan,ENCODE, GTEx and Roadmap Epigenomics Project (Aim 2). We will perform integrated analysis of germ-lineASD variations identified in more than 1000 families from the Simons Simplex Collection to characterize causalenrichments in developmental periods, brain regions, and cell types to better characterize the mechanisms bywhich genetic variation in humans alters brain development and function in health and disease (Aim 3).Completion of these aims will lead to a well-integrated resource across major periods in human cortical andstriatal development that will permit generation of concrete testable hypotheses of ASD mechanisms, andinform our pathophysiological understanding of other related neuropsychiatric disorders.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
