Researchers Discover New Regions of the Genome That Contribute to the Risk of Schizophrenia
Researchers Discover New Regions of the Genome That Contribute to the Risk of Schizophrenia
Researchers now know that over 100 regions of the genome contribute to risk for schizophrenia, and more remain to be found. Each of these comprises a small, common change in the genetic code that incrementally increases risk for the disease.
Now researchers are faced with the hard work of figuring out what exactly each of these genetic changes means to cells in the brain. The changes are single-“letter” irregularities in the 3-billion-letter human genome called SNPs (single nucleotide polymorphisms). New stem cell technologies have begun to allow researchers to explore the effects of SNPs in human neurons grown in a dish.
A new study, published in Molecular Psychiatry November 18th, takes this approach by studying human neurons derived directly from skin cells taken from 24 different people, many of whom were diagnosed with schizophrenia or bipolar disorder. Led by Li-Huei Tsai, Ph.D., at the Massachusetts Institute of Technology, the study focused on a disease-linked SNP within the CACNA1C gene. This gene directs the manufacture of proteins allowing calcium to flow into cells, where it can kick start many different processes, including those that modify wiring between neurons.
Tsai and her colleagues, including Foundation Scientific Council Member and three-time NARSAD Distinguished Investigator Grantee Bruce M. Cohen, M.D., Ph.D., used revolutionary techniques developed over the past few years to induce ordinary skin cells from patients to be “reprogrammed” as neurons. In the resulting collection of so-called induced neurons -- the largest such collection reported to date -- some of the cells had two copies of the disease-linked SNP, others had one, and still others had none. Neurons carrying two copies of the “risk” SNP had higher amounts of CACNA1C, and larger calcium currents flowing into the cell than neurons with one or no copies of the SNP.
The findings suggest that irregularities in calcium channel expression contribute to risk for psychotic disorders, and point to the utility of reprogrammed human neurons for chasing down the biology of other genetic signals detected by studies that search across the genome for disease-related SNPs.
Other NARSAD Grantees participating in this study included 2010 NARSAD Young Investigator Grantee Jon M. Madison, Ph.D., 2006 Young Investigator Grantee Roy H. Perlis M.D., M.P.H., and 2004 Young Investigator Grantee Dost Ongur, M.D., Ph.D.
