Studies on identical twins have long shown how schizophrenia has a strong genetic component. But when researchers look for genes associated with the disease, they are confronted with a profound muddle – hundreds of genes appear to be involved, but upon closer inspection each only confers a slightly higher than normal risk of developing the disease. In other words, researchers don’t know which of these genes is the real culprit.
Recent findings arising from a unique collaboration between researchers at the Weizmann Institute of Science and Shalvata Mental Health Center in Israel suggest a way out of this genetic mire. In their study, the researchers gave first proof to the idea that calcium regulation plays a central role in schizophrenia – which could lead to much better diagnostics.
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Decoding a complex genome
Disease-encoding genes that might account for schizophrenia or other diseases are generally identified in so-called genome-wide association studies. The idea is to compare the genes of thousands of people – patients as well as healthy people – and search for tiny differences of just one or two “letters” in the genetic sequences that make up the genes. If certain variations appear more frequently in those with a disease such as schizophrenia than in the healthy population, one can start asking whether the change in that particular letter is connected to the disease.
But with hundreds of possible genetic candidates, the data dissolve into “noise.” There is little way to tell if the switched letter is an alternate spelling or punctuation, or whether it will be like substituting “pear” for “peach” in a recipe – a slight but possibly significant alteration to the final dish.
‘Filtering’ genes to understand their function
Unraveling this mystery presented a compelling challenge to Dr. Libi Hertzberg, who is no stranger to challenges. Hertzberg was a master’s student under Prof. Eytan Domany and together they teamed up with Prof. Vahram Haroutunian of Mount Sinai Hospital in the US, who has a unique database of information gleaned from post-mortem brains that have been donated to his lab, including those from schizophrenia patients. From these, he can test the levels of the messenger molecules – mRNA – that are produced from the various genes. In other words, scientists can use these data to understand how the genetic information translates into action in various brain cells.
Now the team had two very different sets of information – genes identified in the broad, genome-wide studies and the mRNA levels from the brain database – giving them a sort of “filter” that enabled them to identify the genetic sequences whose slight misspelling was not only associated with the disease but also exhibited interesting patterns of expression in the brain.
The team then began to analyze their narrowed-down list of genes: The approach Domany has developed over the years looks for the actions of groups of genes, rather than searching for the effects of a single gene, and this strategy worked well for the schizophrenia data. Using algorithms he and his team have developed to first identify paired correlations and from these, clusters, they ultimately identified a collection of around 19 genes that clearly stood out from the noise.
Calcium channels are key
Yet the question remained: What does this group of genes do? That question is far from simple: there are hundreds of ways that these genes could interact and thousands of possible effects of their actions. Further computational analysis of the data revealed that the cluster of genes they had identified is associated with the functioning of the cells’ calcium channels. Nerve cells rely on these channels in their membranes to regulate the uptake of calcium ions, which excite the cells to action. Additional tests using information from the genome-wide studies and databases of protein interaction analyses supported their results.
Hertzberg says that these findings give strong backing to the idea that calcium regulation plays a central role in schizophrenia, and adds that the genetic interactions they have revealed might present useful targets for drugs. Domany points out that the next step is to understand exactly how the regulation of calcium signaling goes awry in the disease – a step that will require much more research. But the scientists are hopeful that their results, in addition to pointing to a fruitful approach to understanding how genes contribute to neuropsychological disease might, in the future, lead to both better diagnostics and possible treatments for schizophrenia.
Photos: Giuila Cappelli