Genome Studies Open Window on Schizophrenia Etiology

Genomewide association studies (GWAS) have in recent years identified genetic variants linked to development of schizophrenia, part of a series of rapid advances that have energized the field of psychiatric genetics.

Based on multiple analyses of data from the international collaboration known as the Psychiatric Genome Consortium (PGC)—some of which have been published, and more are soon to be in press—the genetic architecture of schizophrenia is fast emerging, Patrick Sullivan, M.D., a professor of genetics and psychiatry and director of the Psychiatric Genomics Department at the University of North Carolina School of Medicine, told Psychiatric News.

Genetic architecture describes the correspondence between phenotypes (e.g., symptoms) and underlying genotypes (e.g., disease-causing genetic variants), particularly how many different loci are involved and the effects of these loci.

The earlier search for genetic variations with a strong, large effect has turned up only a few significant findings. Although more work is being done, scientists have “looked pretty hard” for variants with large effects and should have found them, according to Sullivan. Rather, it appears that schizophrenia is partly caused by “hundreds of variations in hundreds of different genes, where the effects of each variation are very subtle,” he noted.

Jonathan Sebat, Ph.D., an associate professor of psychiatry and the chief of the Center for Molecular Genomics of Neuropsychiatric Diseases at the University of California, San Diego (UCSD), explained the genetic causes of schizophrenia in a somewhat different way. (Sebat coordinates the copy-number variation [CNV] group in the PGC, which is finishing a separate study on schizophrenia and anticipates its publication within a few months, he told Psychiatric News.)

Previous research has shown that CNVs, which includes deletions or duplications of large chunks of DNA, contribute to schizophrenia as well as to autism and bipolar disorder, and specific CNVs have been located. However, the extent of CNVs’ contribution to psychiatric disorders remains a subject of debate. Sebat estimated that de novo CNV mutations, which are usually seen in only one person in a sample population, contribute to from 4 percent to 5 percent of all schizophrenia cases. “So far all the CNVs associated with schizophrenia [that we know of] are rare variations, none is common,” he explained.

Sebat said that in one patient with schizophrenia, a rare CNV or a few variants could account for the total cause of his or her disease; another patient, also diagnosed with schizophrenia, may have different genetic variants and different biological mechanisms. Do they have the same disease or different diseases that look similar? Often the underlying pathology may fundamentally differ. Therefore, the complexity of psychiatric genetics also lies in the heterogeneity in a symptom-based classification system.

“Symptoms alone have turned out to be not very reliable for predicting the causes of the disorders,” Sebat said. “A constellation of similar symptoms can come from lots of different genetic and biological errors. Until we understand the underlying causes of mental disorders, we cannot correctly reclassify them.”