Wayne E. Crill Endowed Lecture: Kristen Brennand, PhD (Yale University)

Gene x Environment Interactions in Brain Disease

Kristen Brennand, PhD, Professor in Psychiatry & Genetics at Yale University School of Medicine

Abstract: Each person’s distinct genetics and environment predispose them to some phenotypes and confers resilience to others. We seek to understand the genetic regulation of phenotype, and how it is impacted by developmental, cellular, and environmental contexts. Our functional genomics approach integrates human induced pluripotent stem cell models with
CRISPR-based genome engineering to introduce and reverse genetic variation, yielding precision models that can be combined with genetic and pharmacological screens. Given the complex genetic risk architectures associated with psychiatric disorders and neurodegenerative diseases, we ask how diverse risk variants share convergent downstream impacts, and whether when added together, combinatorial perturbations yield outcomes that cannot yet be predicted by individual manipulations alone. Likewise, we ask how stress, inflammation, hormones, and other exposures exacerbate or ameliorate the effect of disease-associated risk factors. We study how genotype-phenotype relationships vary across people and dynamic conditions, within and between the cell types of the brain. Thus, rather than just characterize the impact of trait-associated variants, we seek to uncover modifiers that alter it. Our goal is to decipher the frameworks that buffer genetic risk, in order to confer biological resilience and promote healthy development. Understanding the basic biology governing the complex interplay between genetic variants and the environment will springboard the development of novel, personalized approaches to improve health and prevent brain disease