Massively Parallel Characterization of Cell-type and Context Specific Regulatory Risk Elements Across Psychiatric Disorders in a Stem Cell Model of Neurodevelopment

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There is an urgent need to decipher the complex polygenic risk architecture of neuropsychiatric and neurodevelopmental disorders. Most disease-associated common variants are non-coding. Candidate risk loci in noncoding regions are often regulatory elements, such as enhancers and promoters, that may modulate transcriptional activity of key genes contributing to one or many endophenotypes. The functional impact of most disease-associated non-coding variants remains unknown. Enhancers are known to underlie cell-type specific patterning of gene expression influencing cellular development and responses to environmental conditions. Candidate regulatory sequences (CRS) associated with genetic risk are likely key drivers of underlying endophenotypes and represent potential therapeutic targets. Over the past decade, large-scale identification of regulatory sequences has expanded our awareness and highlighted their importance yet functional characterization of regulatory elements on a meaningful scale remained inaccessible. Only with contemporary advances in high-throughput sequencing and large-scale screening techniques, such as the Massively Parallel Reporter Assay (MPRA), has characterizing the growing list of non-coding risk loci en masse become feasible. I will apply a MPRA in hiPSC-derived brain cells to identify psychiatric risk variants within CRS that demonstrate cell-type specific transcriptional activity. Additionally, I wi/1 lool< at the interactions ol pre-natal stress and inflammation with genetic risl< and consequent susceptibility to negative mental health later in life. There is sufficient evidence correlating fetal environmental factors with neurodevelopmental trajectories. Stress or inflammation during pregnancy has been linked to mental health outcomes in the offspring. The influence of pre-natal environmental factors on brain-related CRSs may explain correlations with Maternal-Immune Activation (MIA) and increased susceptibility to stress and negative health trajectories of the offspring. Biological mechanisms underlying MIA may contribute to this increased susceptibility. Using MPRAs, I will identify risk variants within brain-related CRS that confer greater susceptibility, or resilience, to environmental stressors. By assessing environmental interactions during development, we will look at contributions to risk that precede later-life traumatic experiences or symptom presentations. This research will take place under the Mount Sinai Neuroscience Training Program. Mount Sinai's Department of Neuroscience currently ranks 2nd nationally in NIH funding. Nearly 5,000 ft2 of space are allocated to the Training Program within the Neuroscience Department and Friedman Brain Institute. There is, additionally, ~100,000 ft2 that house the Department's and the lnstitute's research programs and 4,500 ft2 dedicated to Institutional CORE facilities. This fellowship would support my journey to become a multidisciplinary, translational principal investigator by providing training in four major areas: Scientific Excellence. Scientific Alliance. Academic Scholarship. and Scientific Leadership.