genetics of macroscale brain structure
Genetic variants affecting the structure of the human brain may lead to increased risk for neuropsychiatric disorders. Jason is a co-founder of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium, a multinational group of over 300 investigators contributing ~35,000 subjects for genome-wide association meta-analysis of human brain structure measured through MRI. Through our consortium, we identified the first highly significant and replicated common variants that influence macroscale brain structure. For a review of this field of research and future directions, see: Le et al., 2019 and Matoba et al., 2021. For primary research findings, please see: Stein et al., 2010; Stein et al., 2012; Hibar et al., 2015; Adams et al., 2016; Franke et al., 2016; Hibar et al., 2017; Grasby et al., 2020; Matoba et al., 2022.
Genetics of gene Regulation During Development
Expression quantitative trait loci (eQTL) and chromatin accessibility quantitative trait loci (caQTL) studies identify those genetic variants that influence the regulation of genes. Using a population of human neural progenitor cells and developing human brain tissue, we have created developmental and cell-type specific map of genetic variants that influence expression of nearby genes and regulatory elements during the development of the human cortex. For primary research findings, please see Liang et al., 2021, Aygün et al., 2021, Aygün et al., 2023, Lafferty et al., 2023, Liang et al., 2023.
Pharmacogenomics and Gene x environment interactions in a dish
Identifying how inherent genetic variation alters response to clinically useful drugs may allow prioritization of medication based on genetic background. Similarly, identifying how inherent genetic variation alters response to environmental toxicants may allow us to understand the mechanisms by which toxicants impact brain development and function. We apply drugs, environmental toxicants, and stimulate signaling pathways in our cell culture systems with inherent genetic variation. We have identified variants that impact response to these stimuli. For primary research findings, please see Wolter, Le, et al., 2023, Matoba, Le, Valone et al., 2023.
Genetic influences on microscale Brain Structure
We implement tissue clearing approaches to image whole brains of model organisms at cellular resolution. These approaches are complementary to MRI based studies of genetic influences on brain structure because they provide the resolution to quantify individual cells as well as and cell-type specific labeling based on protein expression. We work with Guorong Wu to develop new tools to analyze these images. For primary research findings, please see Krupa et al., 2021, Borland et al., 2021, Kyere, Curtin et al., 2022.
iPSC-derived Cortical organoids from individuals with autism
Induced pluripotent stem cells (iPSCs) are a way of using cells from a research participant and “going back in time” to study how their brain develops. We collect blood from individuals with autism and those without, reprogram those blood cells to an embryonic like state called pluripotency, and then differentiate those iPSCs into cortical organoids - balls of cells that have some features of the developing cortex of the participant from which they were derived. We are using these iPSC-derived organoids to understand the cellular and molecular basis leading to brain overgrowth in individuals with autism, in participants of the Infant Brain Imaging Study (IBIS). For primary research findings, please see Glass et al., 2023.
Gene regulation During human Cortical neurogenesis
The same genes are present in every cell in the body, but each cell-type has distinct functions. There are molecular switches, called gene regulatory elements, that turn genes on and off. These gene regulatory elements allow each cell to produce all the machinery needed to perform its functions. Our work identified gene regulatory elements present during the development of the human cortex that are involved in the production of neurons. We mapped those regulatory elements to the genes they impact and show that genetic variation within those regulatory elements, present early in development prior to birth, impacts adult brain structure and function. Reference of interest: de la Torre-Ubieta, Stein, et al., 2018 and see Preview and Research Highlight.
fidelity of Neural stem cell models
How similar are the cells in a dish to the actual developing human brain? We've developed a bioinformatic system using a rigorous genome-wide statistical framework to determine: (1) how well in vitro models match in vivo development, (2) what level of developmental maturity is achieved after differentiation, (3) what neuroanatomical identity is modeled, (4) what specific neurodevelopmental processes and molecular mechanisms are preserved, and (5) what specific aspects remain to be better modeled in vitro. Reference of interest: Stein et al., 2014.