Disorders Share Risk Gene Pathways for Immune, Epigenetic Regulation

Genome-wide findings add to evidence blurring traditional psychiatric categories

January 29, 2015 • Science Update

Risk genes for different mental disorders affect the same biological pathways, a new and powerful analysis of genome-wide data has found. People with schizophrenia, bipolar disorder and depression shared genetic risk affecting pathways for a key gene expression regulation mechanism, the immune system, and neuronal communication.

“Building on recent evidence of genetic overlap between traditionally-defined mental disorders, the field has now moved a step further, showing how risk gene variants cluster to affect certain shared pathways – further blurring boundaries between diagnostic categories,” explained Bruce Cuthbert, Ph.D., director of the NIMH RDoC Unit, which is reframing research in an effort to identify neurobiological and environmental factors related to the development of specific behavioral symptoms rather than traditional diagnostic categories.  “Narrowing genetic risk to just a few suspect pathways provides clues to shared mechanisms, more accurate diagnosis and, ultimately, more effective treatments.”

Researchers of the Psychiatric Genomics Consortium (PGC) reported the findings of the first large genome-wide study focusing on biological pathways, January 19, 2015 in the journal Nature Neuroscience. Representing more than 500 investigators at more than 80 research institutions in 25 countries, the PGC is funded by NIMH’s Genomics Research Branch.

Recent genome-wide studies revealing overlap in genetic risk that cuts across mental disorders hinted at shared biological processes, such as the workings of certain ion channels, but didn’t systematically focus on these. The PGC Network and Pathway Analysis Subgroup analyzed genome-wide data from more than 60,000 people. Using a new statistical technique called “genetic pathway analysis,” they pinpointed processes through which risk genes cause illness across diagnostic categories.

It turned out that disorders that share a typical age-of-onset, with symptoms first appearing in young adulthood , also shared the same risk gene pathways.  Genes that confer risk for schizophrenia, bipolar disorder, and depression most strongly work through pathways involved in the process of histone methylation, an epigenetic  mechanism that regulates the switching on-or-off of genes in response to environment and experience. Disruption in these pathways prenatally could adversely affect brain development, suggest the researchers.

Risk genes also were found to work via pathways involved in the communication between brain cells, and through effects on the immune system – which other lines of evidence have recently implicated in susceptibility to psychological stress and mood disorders. Additionally, the results suggested that genetic effects on histone methylation appeared to play a more prominent role in bipolar disorder, while effects on neuronal communications may more strongly impact schizophrenia.

Moving beyond identification of individual risk genes to understanding of the pathways through which they work to cause illness moves the field closer to pinpointing new biological targets for future treatments, say the researchers. The study also strengthens the case for using pathway analyses to discover the biology underlying other complex human disorders, they add.

Reference

Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways.  The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium; International Inflammatory Bowel Disease Genetics Consortium (IIBDGC); International Inflammatory Bowel Disease Genetics Consortium IIBDGC. Nat Neurosci. 2015 Jan 19. doi: 10.1038/nn.3922. [Epub ahead of print] PMID: 25599223

Grants

MH101367, MH085520