Jeremy has over ten years’ experience in genetics and bioinformatics, with expertise in gene discovery and systems biology. His work focuses on identifying and leveraging rare mutations for gene discovery in psychiatric disorders—e.g., autism spectrum disorder (ASD), Tourette disorder (TD), obsessive-compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD)—and then applying systems biological approaches that generate and/or integrate multidimensional datasets to understand the biological relevance of these genes and to detect additional risk factors. He developed a novel approach to co-expression network analysis that identified the brain region and developmental time point that showed the strongest convergence of ASD genetic risk, namely, deep layer cortical glutamatergic neurons in the midfetal prefrontal cortex (Willsey AJ et al., Cell 2013). His group followed up this finding by using gene expression data from these brain regions alongside rare genetic variation to increase our power to identify ASD-associated genes (Liu, et al., Mol Aut 2014), and demonstrating that integrating regulatory networks further increases gene discovery (Cotney et al., Nat Commun 2015).
Jeremy's lab has continued to work on ASD rare variant genetics, contributing to the identification of more than 100 ASD associated genes (Satterstrom et al., Cell 2020) and initial attempts to characterize the non-coding architecture of ASD (e.g. Werling et al., Nat Genet 2018; An et al., Science 2018). His group has also expanded to TD, where he recently led work establishing the contribution of de novo variants to TD risk, and similarly utilized recurrent variants to identify novel TD risk genes, including the first two high confidence genes, WWC1 (Willsey AJ et al., Neuron 2017) and CELSR3 (Wang et al., Cell Rep 2018). Systems analyses of these data highlighted cell polarity as a potentially key pathway underlying TD. They are following up these findings with an NIH-funded effort to recruit and genetically characterize 1,000 new TD trios. They have similarly initiated gene discovery in OCD (Cappi et al., Biol Psychiatry 2020) and are now privately funded to recruit and genetically characterize 1,000 new trios. Jeremy's group have also recently become interested in identifying risk genes on chromosome X that contribute to male susceptibility (due to the haploid nature of this chromosome in males). They developed new methods to overcome systematic issues with identification of rare variants on chromosome X, identified a clear signal of male-specific risk, and developed a model that suggests these variants contribute substantially to the longstanding sex bias observed in ASD, TD, and ADHD. They've also developed a framework to leverage these variants for gene discovery and have identified putative risk genes (manuscript in preparation).
To better capitalize on advances in gene discovery Jeremy co-founded the NIH-funded Psychiatric Cell Map Initiative (PCMI) at UCSF, which aims to characterize the functional networks underlying ASD, TD, and other psychiatric disorders and then leverage network-based approaches to generate higher order insights into pathobiology (Willsey AJ et al., Cell 2018). To date, the PCMI has utilized the Xenopus tropicalis vertebrate model system to study, in parallel, the ten most strongly associated ASD risk genes (Willsey HR, et al., Neuron 2021) and generated protein-protein interaction networks for almost one hundred high confidence ASD genes (manuscript in preparation). This work has resulted in specific testable hypotheses around prefrontal cortex development, neurogenesis, and as-of-yet unappreciated points of functional convergence of ASD risk genes.