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.