Bringing Scientists Together to Solve the Mystery of Schizophrenia’s Causation

From The Quarterly, Winter 2015

As a psychiatric geneticist, Dr. Sullivan works to decode the molecular and cellular consequences of the genetic variation underlying schizophrenia. He heads large, multinational projects across a range of disorders, dividing his time between Sweden, where he is a Professor at the Karolinska Institutet, and the University of North Carolina, where he is the M. Hayworth & Family Distinguished Professor of Psychiatry and UNC Professor of Genetics and Psychiatry, as well as the Director of the Center for Psychiatric Genomics.

“When people think about diseases with a genetic cause, they think about Tay-Sachs, Huntington’s disease, cystic fibrosis. These are situations where the genetic note from the orchestra is enormous––a loud, banging drum. If you have a particular genetic variation, you get the disease. If you don’t have it, you don’t get it.”

The speaker, Professor Patrick F. Sullivan, M.D., of the University of North Carolina and Sweden’s Karolinska Institutet, is setting up a contrast. What happens in schizophrenia, he says, could not be more different. “In schizophrenia and other psychiatric illnesses, we haven’t found any loud, banging genetic notes––only far softer notes from many different parts of the genomic ‘orchestra.’ Schizophrenia is a highly complex disease, and while it has a strong heritable component, the genetic factors that contribute to risk are proving to be quite subtle.”

Dr. Sullivan, recipient of a NARSAD Distinguished Investigator Grant in 2010 and in 2014 the Foundation’s Lieber Prize (for schizophrenia research), is one of the leaders of an important movement in psychiatric genomics—the study of genes linked to mental disorders. He and a few colleagues co-founded the Psychiatric Genomics Consortium (PGC) in 2007. At last count, it included some 800 scientists from more than 90 research institutions in 25 countries who have published scientific papers on the genetics of many psychiatric illnesses, as well as genetic factors that several of the illnesses have in common.

“The neat story about the Consortium is that hundreds of investigators have decided to come together and work in a communal way,” Dr. Sullivan explains.“ All the published papers are a sign that the Consortium is working, that we’re moving ahead, and really starting to deliver answers. But back in 2010 and 2011, lots of people in the field were saying that what we were doing was a very bad idea. We completely disagreed and stuck to our guns.”

Most of those who spoke out against the Consortium believed that the PGC scientists were too narrowly devoted to a particular method of probing the human genome called GWAS––genome wide association study. In a GWAS, scientists look for single-letter variations called SNPs (“snips”) in the three-billion-letter human DNA code. SNPs occur frequently across vast swaths of the population. The idea behind the GWAS approach is that a common illness like schizophrenia (which affects about one person in 100, worldwide) most likely is caused by factors commonly shared, which should be seen repeatedly if the genomes of many affected people are scanned.

But while several years of GWASs on schizophrenia turned up hundreds of SNPs that occurred more often in patients than in healthy people, few scientists were convinced. There were two problems, Dr. Sullivan explains. One was that the SNPs found in one GWAS usually didn’t match the SNPs that turned up in the next study. This “reproducibility” problem was related to another problem: “We had always massively underestimated the number of people we would need to look at in these studies in order to get a clear signal from the genes,” he says. This problem of insufficient sample size spurred the formation of the Consortium. The hope was that by pooling many studies that involved large numbers of patients, reproducible genetic signals would emerge.

That is what seems to be happening. Now, rather than conducting a GWAS comparing the genomes of 2,000 schizophrenia patients with 2,000 healthy people, the PGC is amassing samples of, say, 35,000 patients. By the end of the year, the number of schizophrenia patient samples should grow to 60,000 while the total number of samples across psychiatric illnesses could reach 400,000.

In addition to GWASs, which look for commonplace variations, members of the Consortium, including Dr. Sullivan, also conduct studies on rare and ultra-rare variations of the genome. Most involve the abnormal multiplication or deletion of DNA segments at points along the genome. Prior research has shown that people with schizophrenia and autism, for example, have a much greater likelihood of having these rare types of mutations than healthy people. It’s hypothesized that when they occur in areas that contain genes involved in the early development of the brain, they have the potential to cause illness, even in the absence of other causal factors. In contrast, illness-associated SNPs, though commonplace, are thought to contribute a tiny amount to overall risk for becoming ill.

“Whether the genetic clues are rare, common, or both, the point is that we must use all available methods to find them,” Dr. Sullivan says. “As of now, the data are increasingly clear that schizophrenia is a common-variant disease, on average.” This means that in most patients, the portion of the illness traceable to genetic variation is probably due to large clusters of small-effect common variations that are only now becoming visible as vast numbers of patient samples are being brought together for study.

Watch Dr. Sullivan's Presentation at the 2014 Mental Health Research Symposium >

Following Up on Clues From Genes

In July 2014, members of the Schizophrenia Working Group of the Psychiatric Genomics Consortium published a landmark paper in the journal Nature. The many collaborating scientists included Lieber Prize winners Patrick Sullivan, M.D., Michael O’Donovan, M.D., Ph.D., and Michael J. Owen, M.D., Ph.D., as well as Foundation Scientific Council members Kenneth S. Kendler, M.D., and Daniel R. Weinberger, M.D. These senior authors and their colleagues revealed “biological insights” from a genome-wide association study of 37,000 schizophrenia patients, the largest-ever such study.

As headline writers around the world noted, the Consortium had identified 108 loci, or locations along the 23 human chromosomes, where single-letter misspellings of the genetic code were thought to contribute to disease susceptibility. “Susceptibility” is the key word, Dr. Sullivan explains: “Each of the 108 variations increases risk by a little bit. That’s the thing about schizophrenia genetics: it’s an accumulation of small things. It seems each of us inherits some probability of having schizophrenia.”

Results of the study suggest to Dr. Sullivan that common genetic variants––of which many more will likely be found––may, together, account for much of the total genetic portion of risk for schizophrenia. At the same time, it is very likely that in a small percentage of cases––possibly as little as one percent of the total––single rare variations may be disruptive enough to cause illness without contributions from other genetic factors. In addition, the environment is always a factor that contributes in small or large part to risk in individual cases.

Going down the list of 108 newly identified common risk variants identified by the Consortium in July, one is immediately struck by a variation affecting one of the genes (called DRD2). This gene tells neurons how to make receptors, or docking ports, for the neurotransmitter dopamine. Dopamine signaling has been a suspect in schizophrenia for many years, in part because antipsychotic drugs are known to block dopamine receptors. Several genes involved in the transmission of the common signal-carrying molecule glutamate were also implicated.

Perhaps most intriguing, there were associations between some the 108 risk variants and the expression of genes that play important roles in the immune system. Involvement of the immune system in schizophrenia and other neuropsychiatric illnesses has long been suggested. Some scientists have postulated that inflammation and/or infection is in some way related to heightened risk. GWAS findings draw attention to the major histocompatibility complex, a set of cell-surface markers encoded by a group of genes that controls several aspects of the immune response. An immune component of risk reflects the widely acknowledged “environmental” dimension of the total risk picture.

The study illustrates the importance of devoting more time and energy to fleshing out the biological pathways that could be involved in schizophrenia risk. Writing in Nature, two commentators call this effort “a tremendous advance, of the sort that rewrites textbooks.”