Recent genome-wide association studies (GWAS) of schizophrenia and other neuropsychiatric disorders have identified abundant disease susceptibility loci, providing an unprecedented opportunity for developing more effective preventive, diagnostic, and therapeutic strategies. Translating these genomic findings into medicine requires a better understanding of causal molecular mechanisms underlying the genetic associations. Human neurons derived from induced pluripotent stem cells (iPSCs) provide a disease- relevant cellular model for studying the genetic perturbation at these disease risk loci. However, due to variable individual genetic backgrounds, functional assay by directly comparing iPSC lines of different individuals requires a currently unfeasible number of iPSC lines to achieve sufficient statistical power. Genome editing (e.g., CRISPR/Cas9) technology can overcome this difficulty by creating isogenic lines that differ only at a variant site, thus enabling the comparison of allelic function on the same genetic background. The major research goals here are to derive iPSCs from both patients and healthy controls, perform CRISPR editing, differentiate the iPSCs into disease-relevant neurons and study the functional effects of the genetic perturbation at disease risk loci. These projects are funded by NIH grants. For a recent paper, please see: Forest MP et al., Open Chromatin Profiling in hiPSC-Derived Neurons Prioritizes Functional Noncoding Psychiatric Risk Variants and Highlights Neurodevelopmental Loci. Please see most recent publication: Cell Stem Cell. 2017 Sep 7;21(3):305-318.

Three projects Project 1: Develop more effective approach for generating iPSC and differentiating to neuronal subtypes that are relevant to neuropsychiatric disorders

Project 2: Determine the dynamics of epigenomic and transcriptomic changes of iPSC-neuron differentiation and identify regulatory disease risk variants.

Project 3: Carry out CRISPR-Cas9 based genome editing to generate isogenic iPSC lines (and neurons) that carry specific disease risk alleles, and identify the functional effect of the genetic variant(s) on downstream gene pathways/networks as well as neuronal morphological and electrophysiological phenotypes.

The involved methods will depend on the project selected. For wet-bench work related to iPSC generation, neuronal differentiation and CRISPR-Cas9 genome editing, the methods will include cell culture, basic molecular biology techniques, IF staining, open chromatin mapping by ATAC-seq (Assay for Transposase-Accessible Chromatin by sequencing) and RNA sequencing (RNA-seq). Computational work related to transcriptomic and epigenomic profiling will involve developing novel analytic methods and/or using commonly used computation tools.

R package (Lab will have the needed resource)

Weekly lab meetings; journal clubs; annual meetings of the American Society of Human Genetics or World Congress of Psychiatric Genetics.