June 8, 2015

The schizophrenia mosaic: U-M team receives $3.8M grant to study genetic differences

Why does schizophrenia happen, and how can we improve treatment for it? These basic questions persist despite years of research on one of the most puzzling, and debilitating, mental illnesses.

Now, a University of Michigan Medical School team and their colleagues will take a new approach to addressing these questions by searching for genetic clues in postmortem brain tissues of people with and without schizophrenia.

Instead of hunting for genetic problems that these individuals inherited from their parents, they’ll be zeroing in on defects that arose during the individual’s life – which a growing number of scientists think may be crucial to understanding many disorders, including schizophrenia.

Their work will be fueled by a $3.86 million, five-year grant from the National Institutes of Health, in collaboration with researchers at the Lieber Institute for Brain Development and the Salk Institute for Biological Studies.

Together they’ll tackle the issue of “mosaicism” in schizophrenia — the idea that changes in the DNA of a person’s individual brain cells, or in the DNA of their neural stem cells that give rise to brain cells, may contribute to schizophrenia.

Schizophrenia risk is higher in people who have a close relative with the disease, and scientists have identified a small number of gene mutations associated with the risk of schizophrenia. However, the genetic underpinnings of disease risk remain mysterious in a majority of schizophrenic patients.

The idea that mutations and other small changes may make our brains a mosaic of cells, which do not all share the same genetic blueprint, is still an emerging one. But it seems to fit with current knowledge about schizophrenia – including findings from studying people with schizophrenia who happen to have an identical twin. About half the time, the other twin in the pair does not have the condition — despite having inherited identical DNA from their parents.

At U-M, the focus of the new project will be on bulk sequencing of DNA from many cells, in post-mortem brain samples derived both from people with and without schizophrenia, to search for evidence of somatic mosaicism. Colleagues at the other institutions will focus on different aspects of studying mosaicism in schizophrenia.

The team will study tissue from four brain regions implicated in schizophrenia, as well as dural fibroblasts, to look at the genetic "mosaic" that may influence risk of the disease.
John V. Moran, Ph.D., who holds the Gilbert S. Omenn Collegiate Professorship in the U-M Medical School’s Department of Human Genetics and is a Howard Hughes Medical Institute Investigator, leads the U-M research team. He’ll work with Jeffrey M. Kidd, Ph.D. and Ryan E. Mills, Ph.D., Assistant Professors of Human Genetics and Computational Medicine and Bioinformatics, and Kenneth Y. Kwan, Ph.D., an Assistant Professor in Human Genetics and Research Assistant Professor at the Molecular and Behavioral Neuroscience Institute.

The U-M researchers will work with a team at Lieber headed by Daniel R. Weinberger, M.D., and the Salk team headed by Fred H. Gage, Ph.D.

The grant from the National Institute of Mental Health, part of the National Institutes of Health, will build on work from the Gage and Moran laboratories on the “jumping gene” concept. They have shown that genetic changes in the brain—caused by a mechanism called LINE-1 retrotransposition — are more common, and more active, in humans than had been thought.

The experiments conducted by the Michigan team will use brain tissue from the collection held by the Lieber Institute, including brains donated by people who had schizophrenia during their lives and brains donated by those who did not have the condition.

“With this funding, we will test the hypothesis that differences in the genetic composition of neurons within an individual contribute to the development of schizophrenia,” Moran says. “We hope this knowledge will yield a better molecular definition of schizophrenia, aid diagnosis, and offer the potential to identify new drug targets for treating this devastating illness.”

Grant number: MH106892