115. Bridging the “Two Hits”: Toward Mechanisms That Connect Early and Late Neurodevelopmental Risk Periods

Abstract

Overall Abstract: Although schizophrenia typically presents in the second or third decade of life, antecedent events during brain devel-opment, ranging from early in gestation to late in adolescence, are thought to lay a foundation for disease risk. The well-known "two-hit" hypothesis implicates a convergence of environmental and/or genetic insults during two distinct developmental periods-one early and one late. While some have argued that even a "two-hit" model is overly simplistic, there is consensus that schizophrenia involves a dynamic interaction of specific risk factors and brain development. In light of this complexity, unifying mechanisms that link together critical risk periods are particularly important to identify and exploit. Massive and uniformly acquired genomic, gene expression, brain imaging, and clinical data sets have become available in recent years; these collections have provided a vast and accessible search territory for new leads, which can be followed up using high-throughput molecular probes. Here, we will identify some promising threads that are now emerging from this confluence of big data and new technology. Elaborating a novel genomic context for a well-established perinatal risk factor, Daniel Weinberger will describe how the impact of GWAS-derived risk variants is condi-tioned on obstetrical complications and related changes in placental gene expression. Merging postmortem data from BrainCloud with MRI data from the Brain Genomics Superstruct Project, Joshua Roffman will demonstrate the importance of fetal gene expression and meth-ylation to reduced cortical thickness, which is frequently seen in both schizophrenia patients and high-risk individuals. Steven McCarroll will describe how massively parallel single-cell RNA profiling with Drop-seq has identified dozens of cell types with distinct expression profiles; effects of schizophrenia risk genes can be mapped onto these specific cell types throughout neurodevelopment, providing new insights into altered synaptic pruning. Raquel Gur will link neurodevelopmental genes to cognitive and brain imaging data from individuals with 22q11 deletions as well as youth at risk for psychosis from the Philadelphia Neurodevelopmental Cohort. To conclude the panel, Andreas Meyer-Lindenberg will discuss potential relationships among these emerging longitudinal mechanisms, the new technologies that are enabling their discovery, and the potential of this work to yield tractable new targets for prevention and early intervention.