A unique population in northern Finland has helped reveal that schizophrenia, some autism spectrum disorders and other forms of cognitive impairment may all share a common genetic pathway.

In Finland, there exist several small communities that used to live for years in isolation. Amongst the descendants of these groups, otherwise rare genes occur more regularly than elsewhere in the country because a level of inbreeding was almost inevitable.

Nelson Freimer at the University of California, Los Angeles, and colleagues studied one of these communities, where schizophrenia and other neurological disorders are unusually common.

His team first searched for any genetic deletions – chunks of DNA that are missing from a chromosome – that were more common in this group than in the general population. They found a promising candidate on chromosome 22. A deletion on this chromosome was present in 18 of 173 people from this isolated group, but in just one of the 1586 samples taken from people spread throughout the rest of Finland.


Tests confirmed that people with schizophrenia or cognitive impairments were more likely to be missing this chunk of DNA.

Identifying this deletion as a risk factor for schizophrenia and cognitive impairment puts us one step closer to understanding the biological processes at the root of such complex syndromes, says Freimer.

Tying it all together

Further investigation revealed that the deleted region normally contains a gene that makes an enzyme called topoisomerase III beta (TOP3B). This enzyme works to temporarily chop up DNA strands for a process called gene transcription, during which a particular part of the DNA is copied into RNA.

A team led by Weidong Wang from the US National Institute on Aging in Baltimore, Maryland has been exploring the function of TOP3B in more detail. They say that it also has a role in regulating the winding and unwinding of RNA – the first enzyme found to do this in animal cells.

In addition, they have found that TOP3B has a role in the disruptions that lead to fragile X syndrome. Like schizophrenia, fragile X has been linked to abnormal brain development.

Although the researchers do not yet know how disruptions in TOP3B may affect brain development, they say the most likely explanation is that it changes the shape of the RNA, and thereby disturbs which RNA molecules get copied into proteins. This could cause neurons to grow and connect in a haphazard way. Disrupted neuronal connections have been associated with schizophrenia, autism and intellectual disability, so this could explain why a deletion of the TOP3B gene is associated with all three, says Wang.

Journal reference: Nature Neuroscience, DOI:10.1038/nn.3484;

Nature Neuroscience, DOI: 10.1038/nn.3479