Here’s how genetic medicine was supposed to work. Once the basic menu of human genes was mapped by the Human Genome Project, scientists could turn their attention to gene variants associated with common diseases. These disease-associated variants had to be relatively common; according to the “common disease, common variant” theory, rare variants with negative effects would quickly be removed by natural selection. So hundreds of studies – called genome-wide association studies, or GWAS – were organized to compare common gene variants in people with and without a specific disease or trait. Once the gene variants associated with heart disease, diabetes, or psychiatric disorders were found, treatments to cure those diseases would follow.
But ten years later, that simple process hasn’t quite worked as well as hoped. GWAS has revealed some 400 gene variants responsible for traits and diseases. But for many of the largest medical targets, the GWAS results have fallen far short, finding variants that only explain a small fraction of the disease. For a highly heritable disease such as schizophrenia, which afflicts both members of an identical twin pair 60 percent of the time, this is a mystery. The gap between GWAS and twin studies inspired an influential 2008 Nature news story with a headline worthy of the Hardy Boys: The Case of the Missing Heritability.
One place where scientists are looking for their lost heritability has to do less with the content of a gene variant than how often it appears in a person’s genome. Copy number variants, or CNVs, are errors of replication in the genetic code where stretches of DNA are deleted or duplicated, leaving behind zero copies of a genetic region, or two copies, or even more. These copy errors are more common than traditional gene mutation (100 to 10,000 times more frequent), and some CNVs can have dramatic consequences.
“These are very frequent events,” said Elliot Gershon, professor of psychiatry and human genetics. “They are important causes of disease and they turn out to be important causes of neuropsychiatric diseases.”
Schizophrenia is one disease where several CNV associations have been found in recent years, including the latest, published last week in Nature. Gershon, whose laboratory has studied the genetics of schizophrenia and bipolar disorder, contributed “interpretation of data” to the new study and said that it adds more weight to the argument that rare copy errors, not only common variants, can be important drivers of common diseases.
“The importance of a finding like this is that rare mutations were not thought to be generally a cause of common disease,” Gershon said. “But this is another rare variant that can cause schizophrenia.”
The new CNV, a duplication found on chromosome 7, was found in 29 of 8,290 schizophrenic patients tested in the study, compared to only 2 of 7,431 controls. It’s notable, Gershon said, for being a duplication rather than a deletion – instead of eliminating genes, it appears to increase the transcription of one specific gene, called VIPR2. This gene also implicates a previously unrecognized target for potential schizophrenia therapy, the vasoactive intestinal peptide system, previously associated with brain functions such as circadian rhythms and secretion of the hormone prolactin (involved in lactation and some sexual behaviors).
But given that the chromosome 7 CNV was found in only 0.35 percent of schizophrenic patients tested, the new discovery adds only another small sliver to the narrow strip of heritability discovered thus far for the disease. Roughly 5 percent of schizophrenia can currently be accounted for by rare CNVs and new CNV mutations, Gershon said, roughly equal to the amount that can currently be explained by gene variants discovered through GWAS. That leaves the majority of schizophrenia’s genetic origins still to be found, perhaps via studies utilizing next-generation sequencing and gene-gene interactions, Gershon wrote with Ney Alliey-Rodriguez and Chunyu Liu in a recent perspective article on life “After GWAS.” These methods could collect the pieces of a “common disease, multiple rare variant” theory of schizophrenia and other conditions.
Finding more of the rare variants that account for “missing heritability” may help develop diagnostics and treatments for schizophrenia. But it may also fragment the disease we currently think of as schizophrenia into multiple more specific – and rare – disorders, each with their own unique origins and treatments. As Nature reporter Brendan Maher wrote in The Case of the Missing Heritability:
“Medicine tries hard to lump together a complex collection of symptoms and call it a disease. But if thousands of rare genetic variants contribute to a single disease, and the genetic underpinnings can vary radically for different people, how common is it? Are these, in fact, different diseases?”
To be sure, that knowledge could eventually help develop more effective, personalized treatments. But in the short term, it may be that genetic medicine’s effect on common disease is to teach us that those diseases weren’t so common after all.