Researchers have identified nearly 700 genes whose activity levels differ in the brains of people with schizophrenia compared to individuals without the disorder. Most of the differences they found were subtle, consistent with the idea that variations in many genes contribute to the risk of schizophrenia, each alone having a small effect.

Many of the genes identified in the analysis fall within DNA regions that were associated with schizophrenia in a large genome-wide association study reported in 2014. Such studies look for genetic variations seen frequently across large numbers of people, both healthy people and those diagnosed with a particular illness.  

The new findings, published September 26 in the journal Nature Neuroscience, report the largest catalogue of genetic influences on brain gene expression and begin to illuminate the biological consequences such genetic variations associated with schizophrenia. This publicly available catalogue (https://www.synapse.org/CMC) will markedly facilitate understanding functional effects and underlying mechanisms across many brain disorders.

Major clues into the genetic origins of the schizophrenia came in 2014, when a team of scientists from the Psychiatric Genomics Consortium analyzed the DNA of more than 140,000 people, including 37,000 with the disorder. That study associated DNA variation at 108 regions in the genome to schizophrenia although it could not pinpoint specific genes.

In the new study, a team of researchers led by Pamela B. Sklar, M.D., Ph.D., a NARSAD 1995 and 1998 Young Investigator and 2006 Independent Investigator and BBRF Scientific Council Member at the Icahn School of Medicine at Mount Sinai, took a complementary approach to understanding the origins of the disorder. Instead of comparing DNA sequences in people with and without the mental illness, the team examined in people with and without schizophrenia the activity of genes within the brain.

Their experiments compared levels of gene activity in the brains of 258 people with schizophrenia to that of 279 people without the illness, using tissue samples collected after patients’ deaths. The analysis identified 693 genes whose activity was different in the two groups. The differences were subtle, consisting of gains or losses of up to about 33 percent of activity.

Notably, Dr. Sklar and her colleagues used their well-powered catalogue to identify the likely genes responsible for the associations with schizophrenia in 19 of the 108 genome locations found in the 2014 study. These genes are particularly likely to be relevant to schizophrenia’s effects on brain function, the researchers say.

Dr. Sklar and her colleagues used their data to identify several genes for follow-up studies in animals. They manipulated the activity of five of the schizophrenia-linked genes in zebrafish (a “model organism” often used for genetics experiments), and found three genes whose alteration disrupted brain development. Other researchers can now extend the team’s findings by further exploring genes on the list to begin teasing out the molecular basis of schizophrenia.

The following NARSAD scientists also contributed to the research: 2013 Young Investigator Panagiotis Roussos, M.D., Ph.D.; 2015 Young Investigator Douglas Ruderfer, Ph.D.; 2013 Young Investigator Edwin C. Oh, Ph.D.; 2013 Young Investigator Eli Ayumi Stahl, Ph.D.; 1997 Young Investigator Scott E. Hemby, Ph.D.; 2010 Distinguished Investigator and 2014 Lieber Prizewinner Patrick F. Sullivan, M.D., FRANZCP; 2006 Young Investigator Shaun Matthew Purcell, Ph.D.; 1999 Distinguished Investigator, BBRF Scientific Council Member, and 2009 Lieber Prizewinner Raquel E. Gur, M.D., Ph.D.; 2002 Young Investigator and 2010 Independent Investigator Chang-Gyu Hahn, M.D., Ph.D.; 2008 Distinguished Investigator, BBRF Scientific Council Member, and 2005 Lieber Prizewinner David A. Lewis, M.D.; 1996 Distinguished Investigator Vahram Haroutunian, Ph.D.; 1994 Young Investigator Barbara K. Lipska, Ph.D.; BBRF Scientific Council Member Joseph D. Buxbaum, Ph.D.; 2012 Young Investigator and 2016 Independent Investigator Kristen Jennifer Brennand, Ph.D.