Genome study turns up new clues for schizophrenia

Image courtesy of Bang Wong, Broad Communications
 

Psychiatric disease exacts an overwhelming human toll, derailing the lives of its sufferers and their loved ones. While more effective therapies offer future hope of relieving this suffering, a key stumbling block is the lack of fundamental knowledge of disease biology: what causes psychiatric diseases and, in turn, what can be done on a molecular level to help alleviate them.

Now, researchers in the International Schizophrenia Consortium (ISC) have taken a critical step forward in this effort by discovering that a large number of common genetic variations influence a person’s chances of developing schizophrenia. All told, such variants may help explain a significant fraction — at least one-third — of an individual’s risk of getting the disease. Their work, together with similar studies led by two other groups, appears in the July 1st advance online edition of the journal Nature.

“While our study finds a surprising number of genetic effects, we fully expect that future work will assemble them into meaningful pathways that will teach us about the biology of schizophrenia and bipolar disorder,” said Pamela Sklar of the Massachusetts General Hospital (MGH) Department of Psychiatry and Center for Human Genetic Research (CHGR), a senior associate member of the Broad Institute of MIT and Harvard, and corresponding author of the Nature paper.

The findings are indeed historic: genome-wide methods have previously been applied to schizophrenia in recent years, and each time struggled to uncover strong evidence that common DNA variations are involved in the disease. The aim of these approaches is to scour the human genome for common genetic differences (known as single nucleotide polymorphisms or “SNPs”) that are found more commonly in schizophrenia patients compared to those without the disease. Those SNPs can serve as markers that point to critical genes and biological processes that influence schizophrenia.

The unusual success of the current study was driven by the use of enhanced statistical methods and the willingness of consortium researchers to share the several thousand patient DNA samples needed for robust results.

The ISC scientists were particularly interested by their discovery that many of the genetic variants implicated in schizophrenia are also implicated in another devastating psychiatric disease — bipolar disorder. That finding gives molecular credence to the idea that these two diseases, generally considered distinct yet related conditions, share some common underpinnings.

“Over the past two years, the consortium has taken important steps towards unearthing the complex genomic architecture of schizophrenia and other psychotic disorders, and this paper is another example of that critical work,” said Edward Scolnick, director of the Stanley Center for Psychiatric Research at the Broad Institute, a major funder of the ISC study. “To fulfill the promise of these early studies, we as a community will need to continue to fully define the genetic basis of these disorders and ensure that our insights help improve the diagnostic and therapeutic options for patients and their families.”

Indeed, there is still much more work yet to be done before the paper’s findings can have an impact on clinical care. The ISC researchers provide evidence for a large number of genetic variants involved in schizophrenia but additional studies are required to specifically pinpoint their genomic locations — and to dissect their roles in psychiatric disease, “How these genetic variants translate into schizophrenia or bipolar disorder for a given patient is not yet known,” said co-corresponding author Shaun Purcell, also of MGH Psychiatry and the CHGR, and an associate member of the Broad Institute.

But, despite the long road that lies ahead, the papers published today by the ISC as well other groups in the schizophrenia research community are certainly a remarkable step toward unraveling the complex biology of these devastating disorders.

As the ISC researchers acknowledge in their paper, “the scores [of genetic variants] derived here have little value for individual risk prediction, meaning that application to clinical genetic testing for schizophrenia would be unwarranted. In the future, measures of polygenic burden, along with known risk loci and non-genetic factors…could open new avenues for studying gene-gene and gene-environment interplay.”

Several other researchers at the Broad Institute and its Stanley Center for Psychiatric Research contributed to the ISC’s Nature paper, including Kristin Ardlie, Kimberly Chambert, Mark Daly, Stacey Gabriel, Finny Kuruvilla, Douglas Ruderfer, Jennifer Stone, and members of the Broad’s Biological Samples and Genetic Analysis Platforms.