genetics of macroscale brain structure

Genetic variants affecting the structure of the human brain may lead to increased risk for neurospsychiatric illnesses. Jason is a co-founder and an active member 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. For primary research findings, see: Stein et al., 2012; Hibar et al., 2015; Adams et al., 2016; Franke et al., 2016; Hibar et al., 2017.

 
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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.

 

Genetics of gene expression

Expression quantitative trait loci (eQTL) studies determine genetic variants that influence the expression of genes. We aim to create a map of genetic variants that influence expression of nearby genes during the development of the human cortex. 

 
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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 give 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.