DISSECTING THE GENETIC BASIS OF SCHIZOPHRENIA USING FUNCTIONAL GENOMICS AND PLURIPOTENT STEM CELL MODELS

Schizophrenia (SCZ) is a highly heritable mental disorder with thousands of associated genetic variants located mostly in the noncoding space of the genome. Translating these associations into insights into the underlying pathomechanisms has been challenging because the causal variants, their mechanisms of action, their target genes and their joint impact remain largely unknown. In this talk, I will discuss our efforts to address these challenges from three complementary angles. To understand the function of individual genetic variants, I will present our work on massively parallel genetic variant screening and functional annotation in induced pluripotent stem cell (iPSC) derived neuronal cell types. In addition, I will share our recent results on leveraging large cohorts of iPSC derived neurons from deeply phenotyped patients as in vitro models of polygenicity. In this context, we sought to translate the effects of highly heterogenous polygenic risk across individuals into common molecular mechanisms underlying the etiology in SCZ, identifying several molecular, cellular and circuit level endophenotypes as points of convergence. Lastly, I will discuss our newly developed strategies to link these molecular and cellular alterations to patient level intermediate phenotypes such as aberrant EEG patterns and cognitive impairment.