Study points to genetic causes of schizophrenia

August 1, 2008 — Even though scientific evidence has long hinted that schizophrenia has a genetic basis, no study has definitively proven that this is the case. Now researchers at the University of North Carolina at Chapel Hill, as part of an international team, have developed the first hard lead into the genetic causes of schizophrenia.

The study – the largest of its kind – identified genetic variants that can increase the risk of developing the disease as much as 21-fold. It also showed that schizophrenia patients are much more likely than normal individuals to have a large number of genetic variants distributed throughout their genomes.

These findings, published online this week in the journal Nature, give researchers a starting point to investigate the underlying biology of the disease. The research also provides hope for people affected by schizophrenia – showing that there is a reason for their illness and that new treatments may be within reach.

“My hope is that by recognizing the genetic causes of schizophrenia, we may begin to see a shift in how our society perceives the mentally ill,” said study co-author Patrick F. Sullivan, M.D., Ray M. Hayworth and Family Distinguished Professor of Psychiatry in the department of genetics at the UNC School of Medicine.

Schizophrenia is a chronic and often devastating brain disease that affects one person in every 100 in the course of their lives. Scientists believe that schizophrenia has many causes – some genetic, some environmental. Despite the many scientific investigations into the topic, little has been learned about the genetics of the disease.

Advances in technology have made it possible to examine genetic variation at a level that was never before possible. In this study, the researchers were interested in a form of genetic variation that relates to the number of specific genes each of us carries in our DNA. People usually have two copies of each gene, one inherited from a father and the other from a mother.

But recently, researchers discovered that healthy people can occasionally have fewer, or more, than two copies of a gene. A person might have three copies at one spot in his genome, sixteen at another spot, or one at another.

“Every person has their own set of copy number variants,” Sullivan said. “Most of these variants are innocuous, but a few can cause disease.”

Sullivan and other investigators in the International Schizophrenia Consortium used new “genechip” technology to look for variations in copy numbers in 3,391 individuals with schizophrenia and 3,181 comparison subjects without schizophrenia. The chips measured the number of copies possessed by the research subjects at 1.8 million different places scattered across the human genome.

The researchers pinpointed three areas of the genome where some of the subjects with schizophrenia had one copy instead of two. The first was a section of chromosome 22, one of the 23 pairs of chromosomes that comprise the human genome. Subjects with fewer copies than normal of this particular chunk of genetic material had a 21-fold increased risk of developing the disease. The second area, on chromosome 15, was another potent risk factor and increased the risk 18-fold. The third area, on chromosome 1, was the weakest of the three but still increased the risk six-fold.

Each of these variations was rare; the most common, the area on chromosome 22, was found in only three out of every 1,000 schizophrenia patients studied. Nonetheless, their ability to increase the risk of developing the disease was very strong.

“These are among the strongest risk factors every identified for schizophrenia,” Sullivan said.

In addition, the study discovered that individuals with schizophrenia have on average 15 percent more regions with copy number variations than healthy individuals. Research is ongoing to determine how these structural variations contribute to the origins of the disease.

The investigators in the consortium are currently taking a closer look at the newly identified areas on chromosomes 22, 15, and 1. The 57 genes contained in these regions of the genome are now considered to be prime candidates of causes of schizophrenia. They plan to sequence individual bases – the As, Gs, Ts and Cs that make up the language of the genetic code – in the schizophrenia subjects to detect the exact differences that exist between them and their healthy counterparts.

“Clearly we have a lot of leads to follow up on,” Sullivan said. “We have generated more work than any one lab could do.”

While it would be premature to apply this research to test for who will develop schizophrenia, it may lead to new treatments for the disease. The researchers hope to connect these genetic changes to a particular cascade of events – a developmental pathway – that leads to schizophrenia. They could then look for compounds that could augment or suppress this pathway as novel medications for the illness.

Funding for the studies led at UNC came from the National Institutes of Mental Health, the Sylvan C. Herman Foundation and the Stanley Medical Research Institute.

In addition to those from UNC, the consortium includes investigators from the University of Aberdeen, Cardiff University, the University of Edinburgh, Karolinska Institutet, Massachusetts General Hospital, the Queensland Institute of Medical Research, the University of Southern California, the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and MIT, Trinity College Dublin and University College London.

Note: Sullivan can be reached at (919) 966-3358 or

School of Medicine contacts: Clinton Colmenares, (919) 966-8757, or Les Lang, (919) 966-9366,