The past decade has seen seismic shifts in the field of psychiatric disorder research in large part due to rapid advances in gene discovery and systems biology. Our understanding of the genetic architecture of disorders such as autism spectrum disorders (ASD), intellectual disability (ID), epilepsy (EP), schizophrenia, and Tourette disorder (TD), has increased dramatically, and continues to do so at a swift pace. For example, our group recently identified 65 genes strongly associated with ASD.
Despite the advances, there remains a vast gap between such genetic discoveries and actionable clinical insights, as we have translated relatively little of these genetic findings to a specific understanding of the underlying biology of these complex disorders. We are beginning to make headway in this area, as, for example, we now have strong evidence that midfetal prefrontal cortex and deep layer glutamatergic neurons play a role in ASD However, it is still unclear if there are other cell types involved, if there is a circuit level phenotype, and most importantly, what pathways and cellular functions are affected.
In an effort to narrow the gap, the Willsey Lab’s research focuses not only on generating insights from the realms of gene discovery and system biology but also, critically, building from these insights to elucidate the biological foundations of psychiatric disorders.
We currently are pursuing three major projects. The first, in order to move beyond the genome and explore the underlying biology of ASD, is to map the physical interactome of the most strongly ASD-associated genes. Our methods include human neurons derived from induced pluripotent stem cells (iPSCs), mass spectrometry (in collaboration with the Krogan group at UCSF), and ChIP-Seq. Characterizing the higher order physical modules of the proteins encoded by these genes will bring us closer to a pathway-level understanding.
The second project, to compliment the first, is to generate and analyze gene co-expression networks, utilizing 3D models of human cortex development, CRISPR-based genetic techniques, and (in collaboration with the Pasca group at Stanford University). We will integrate the protein-protein and protein-DNA interaction networks from the first project with the co-expression networks from the second in order to fully leverage these data.
Our third project focuses on Tourette Disorder (TD). We are utilizing the powerful, systematic gene discovery framework based on the identification of recurrent de novo mutations, that has revealed genes associated with other genetically complex neurodevelopmental disorders (e.g., Bilgüvar et al., 2010; Carvill et al., 2013; Deciphering Developmental Disorders, 2015; Epi4K et al., 2013; Rauch et al., 2012), including the 65 genes already discovered in ASD (De Rubeis et al., 2014; Iossifov et al., 2014; Sanders et al., 2015; Willsey et al., 2013). Eventually, we hope to apply the methods we are developing in our ASD projects to discover the biological underpinnings of TD.
The Willsey Lab believes these projects can serve as a paradigm for understanding any complex genetic disorder. Though each project differs in specifics, they are unified by a commitment to high-throughput design, hypothesis-naïve approaches, and biological validation. Broadly speaking, this is illustrative of the mission of the Willsey Lab: to investigate the foundational biology of psychiatric disorders, and eventually neurodegenerative disorders, by utilizing high throughput, cutting edge techniques, while maintaining a high level of scientific rigor, in order to bridge the crucial gap in knowledge between the genome and the clinic. Ultimately, we seek to both advance the scientific and medical communities’ understanding of these important disorders, and to provide the necessary building blocks for effective future therapeutics.