Genetics of brain disorders

Autism and schizophrenia are neurodevelopmental and psychiatric conditions that affect millions across the globe. While we lack a fundamental understanding of the underlying mechanisms, there is a growing consensus that genetics play a major role in determining one’s risk, and that this genetic risk may manifest early during prenatal brain development. Around the same time that these concepts were becoming popular in the field, revolutionary stem cell technologies enabled researchers to build models of the prenatal human brain in cell culture dishes for experiments.

We are experiencing a golden era of neurobiology that has the potential to uncover the prenatal processes that lead to a wide array of brain conditions.

A subset of autism and schizophrenia cases are caused by rare but powerful mutations that disrupt the functions of key neurodevelopmental genes. To improve our understanding of these scenarios, our team determines how neural cells engineered to harbor these mutations differ at the molecular and cellular level from control cells with the hopes of identifying targets for future treatments. We recently described what happens when cells and people have mutations in the CACHD1 gene and are currently characterizing over 100 other risk genes as members of the NIMH SSPsyGene consortium.

Sometimes, mutations do not affect just a single gene, but rather many genes that are close to each other in the genome. These mutations—known as copy number variants (CNVs)—can disrupt 30-50 genes at the same time. Our team studies the impact of 16p11.2 deletion, which is one of the most common CNVs associated with neurodevelopmental disorders. We are investigating the impact of this large mutation on gene expression and cellular traits relevant to early neurodevelopment using cell villages composed of patient and neurotypical control neural cells. To take things a step further, we are moving beyond the convention of studying cells sitting idle in a dish by exposing villages to important signaling proteins and assessing how patient and control cells differentially respond to these endogenous molecules that orchestrate fetal brain development. We hypothesize that this approach to studying the dynamic molecular and cellular features associated with patient cells will improve our changes of detecting defects that can be rescued through future drug development.