A new study implicates two cellular pathways in schizophrenia risk that haven’t been well supported by genetic evidence before. They involve processes related to the birth of new nerve cells, called neurogenesis, and cell-to-cell signaling by a neurotransmitter called acetylcholine.

The study, published October 19 in Nature, characterized interactions between genome segments that regulate genes, called regulatory elements, and the genes they regulate – which are often located at distant sites on chromosomes.  This occurs because our genetic material is almost unimaginably compressed inside the nucleus of each of our cells, and twists and turns in the “packaged” form of DNA often brings genes and genome sites that regulate them into close proximity even though they are not adjacent to one another.

The study, whose first author was Hyejung Won of the University of California, Los Angeles, and was led by 1999 NARSAD Young Investigator grantee, 2015 NARSAD Distinguished Investigator grantee, and 2012 Ruane Prizewinner, Daniel Geschwind, Ph.D., of UCLA, revealed that 65% percent of regulatory elements called gene enhancers did not, in fact, interact with adjacent genes as is often assumed. When integrating new data on interactions of genes and regulatory sequences, the team found approximately 500 new candidate risk genes that were previously obscured because of their physical distance on the genome from sites where risk genes themselves are located.  Much more work will need to be done to know which of these 500 genes do in fact impact schizophrenia risk. But prior to the new research, these 500 had not been suspected of having such impact.

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The findings bring new insight to the biological function of small variations within parts of the genome that aren’t involved in instructing cells to manufacture proteins – so-called “non-coding” regions of the genome. Such regions are where most of the 108 schizophrenia risk regions identified in a landmark genome-wide association study (GWAS) were found in 2015.  The location of the 108 risk regions in these uncharacterized regions of the genome has made it difficult to understand what genes the risk markers affect, and how they may contribute to the development of schizophrenia.

Insights from the new research were made possible in part by the use of a new technology, called high-resolution 3D chromosome confirmation capture (Hi-C). The technique identifies physical contacts formed by the 3-dimensional folding of DNA when packaged into bundles called chromatin, allowing researchers to resolve interacting parts of the genome including distant genes that could come into contact with schizophrenia-related risk regions in non-coding regions.

“This work shows how feasible it is and how instrumental it is to integrate these data, and how powerful that can be to take the GWAS results to the next level of mechanism and understanding,” says Dr. Geschwind.

TAKEAWAY: New risk genes for schizophrenia have been discovered by researchers using a new method of studying our genetic material, DNA, in the form in which it is found inside the nucleus of our cells. Such DNA is highly compressed and packaged in bundles called chromatin. The packaging brings distant segments of the genomes into close encounter, and occasionally, interaction.