Investigating Genetic Risk for Schizophrenia Using Neuronal Differentiation

What's the science?

Complex genetic variation contributes to psychiatric disorders like schizophrenia. Many single nucleotide polymorphisms (small commonly occurring changes in DNA) together contribute to risk for a psychiatric disorder. A major challenge is to understand how this “polygenic risk” (i.e. the cumulative risk across many regions of the DNA) affects biological pathways that contribute to brain function and disease. This week in Biological Psychiatry, Ori and colleagues explored whether an in vitro experimental model of neuronal differentiation can be informative to study polygenic risk of psychiatric disorders.

How did they do it?

The authors cultured human neural stem cells as they differentiated into neurons over a 30 day period. The authors measured gene expression across the whole genome at 7 timepoints during this period in order to capture changes to the function of genes over time. They first identified genes that have significant changes in expression during differentiation, and subsequently clustered these in separate groups based on their patterns of expression. They next integrated the identified gene expression ‘profiles’ with known risk polymorphisms for psychiatric disorders using information from previously published genome-wide association study (GWAS) data. Namely, they tested if the genes active during differentiation were associated with polygenic disease risk.

What did they find?

They found that gene expression of neuron specific genes generally increased over the course of cell differentiation into neurons. The pattern of gene expression in these developing neurons matched the gene expression patterns documented in the developing human brain (i.e. in vivo instead of in vitro). They next identified thousands of genes that change their expression throughout differentiation. These could be grouped into 8 distinct gene clusters. When they investigated further, they found that genetic risk of multiple psychiatric disorders is significantly associated with gene clusters that are up-regulated during differentiation, with the strongest signal for schizophrenia risk in genes involved in synaptic function. They further replicated their main findings in an independent dataset.   

What's the impact?

This is the first study to examine how polygenic risk for psychiatric disease is associated with gene expression changes in an in vitro experimental model of neuronal differentiation. Many small variations throughout the genome contribute to genetic risk for psychiatric disease, and there is a need to understand how alterations act in concert and predispose one to disease. Unlike other organs, there is limited accessibility to the brain in living individuals. Therefore, there is a need for alternative models that capture and allow for the study of genetic risk of psychiatric disorders. This study puts forward a framework that helps to link schizophrenia polygenic risk to a distinct biological pathway, which now can be further modeled in a controlled laboratory environment.

Ori et al., A longitudinal model of human neuronal differentiation for functional investigation of schizophrenia polygenic risk. Biological Psychiatry (2018). Access the original scientific publication here.