Kristen Brennand, PhD

Each person’s distinct genetic, epigenetic, and environmental risk profile predisposes them to some phenotypes and confers resilience to others. My laboratory seeks to decode highly complex genetic insights into medically actionable information, better connecting the expanding list of genetic loci associated with human disease to pathophysiology. Our goal is to improve diagnostics, predict clinical trajectories, and identify pre-symptomatic points of therapeutic intervention.

Towards this, we employ a functional genomics approach that integrates stem cell models and genome engineering to resolve the impact of patient-specific variants across cell types, genetic backgrounds, and environmental conditions. Individually small risk effects combine to yield much larger impacts in aggregate, but the interactions between the myriad variants remain undetermined. Is there a “tipping point” between health and disease? Can ameliorative early interventions “untip” genetic disease risk? We seek to uncover disease-associated interactions within and between the cell types of the brain, querying the impacts of complex genetic risk within increasingly sophisticated neuronal circuits. Thus, we strive to translate risk “variants to genes”, “genes to pathways”, and “pathways to circuits”, revealing the convergent, additive, and synergistic relationships between risk factors within and between the cell types of the brain.

Even for highly penetrant mutations, a spectrum of phenotypes exist. We hope to understand the genetic, cellular, and environmental contexts that buffer genetic risk, and in doing so, develop interventions to help individuals achieve their greatest phenotypic potential. Thus, the variable penetrance of risk variants can be reframed as phenotypic resilience, evidence of biological “cures” capable of limiting, modifying, or preventing disease in individuals with otherwise high genetic predispositions. Such insights could identify therapeutics tailored to an individual’s specific risk profile, and so springboard the development of novel, personalized approaches to treat disease.