Year: 2023
Type: book-chapter
Abstract: Psychiatric disorders are highly polygenic, with estimated contributions from hundreds to thousands of causal variants, across the allelic spectrum.Interpretation of such a widely distributed genetic risk architecture is a daunting challenge, as no single locus can explain disease etiology, yet it is also critical for mechanistic understanding and clinical translation.Systems biology can begin to contextualize genetic risk variation within our understanding of the hierarchical organization of the human brain, encompassing its cognate underlying cellular pathways and gene regulatory networks, cell types and states, cell-cell interactions, circuit-level function, and ultimately behavior.This chapter provides an overview of how high-throughput molecular "omic" profi ling coupled with network-level inference can provide a framework for biological contextualization of established genetic risk factors to elucidate convergent disease mechanisms.Successes are highlighted leveraging systems biology to prioritize synaptic and chromatin complex genes, and next steps are enumerated to further the translational utility of these approaches. State of ConvergenceHow can we begin to disentangle the relationship between hundreds to thousands of unique variants on complex brain-level cognitive and behavioral phenotypes?A key insight comes from the observation that for complex polygenic disorders, risk genes and molecules, although dispersed throughout the genome, often coalesce within specifi c "core" molecular pathways and cellular networks (Gilman et al. 2012; Parikshak et al. 2015).For psychiatric disorders, some of the fi rst such glimpses were observed among rare syndromic forms of ASD, which appeared to converge at the synapse (Zoghbi 2003).As additional high-confi dence ASD risk variants were subsequently uncovered through copy number variant profi ling and WES, other pathways were implicated, including chromatin remodeling and gene regulation, in addition to synapse formation, neuronal cell adhesion, ubiquitination pathways, and targets of Fragile X mental retardation protein (FMRP), among others (De Rubeis et al. 2014; Glessner et al. 2009; Iossifov et al. 2014; Pinto et al. 2010; Sanders et al. 2015; Satterstrom et al. 2020).In SCZ, although the overall contribution of rare loss-of-function variation is smaller, similar convergence has been observed among synaptic and chromatin gene sets (Figure 11.1), as well as glutamate signaling, and FMRP targets, in particular (Fromer et al. 2014;
Source: The MIT Press eBooks
Author: Michael J. Gandal
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W4386633731