Contextualizing Convergent Common Variant Mechanisms through Systems Biology

Excerpt

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” profiling 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.