Schizophrenia is a distressing disorder involving hallucinations, delusions, paranoia and agitation. It affects around one in 100 people in the U.S., with symptoms usually first appearing between the ages of 16 and 30. Its causes have long been debated, particularly regarding whether genetics plays a role. It is known to be highly heritable, but small sample sizes and other methodology hurdles stymied early attempts to discern a genetic link.
Now the biggest-ever genetic study of mental illness has found 128 gene variants associated with schizophrenia, in 108 distinct locations in the human genome. The vast majority of them had never before been linked to the disorder. This finding lays to rest any argument that genetics plays no role.
The study, published in July in Nature, is the result of a collaboration among more than 300 scientists from 35 countries, named the Schizophrenia Working Group of the Psychiatric Genomics Consortium. The researchers compared the whole genomes of nearly 37,000 people with schizophrenia with more than 113,000 people without the disorder, in a so-called genome-wide association study (GWAS). Genetic material, or DNA, is made up of a sequence of molecular pairs, thousands of which string together to form genes. The GWAS involves tallying known common mutations in these pairs, in people with and without a condition. Variants that show up significantly more often in people with the condition are said to be “associated” with it. The GWAS “potentially provides a more comprehensive view of the biological players in disease than previous genetic studies,” says Benjamin Neale of the Broad Institute in Cambridge, Mass., one of the study's lead authors.
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The technique cannot identify the exact mutations that cause illness or even pinpoint specific genes. Rather it flags areas of the genome that contribute to risk. Genes in these regions warrant further investigation to uncover the biological processes underlying the condition. “We've prised open lots of windows for people to climb in and attack the biology of schizophrenia,” says Michael O'Donovan of Cardiff University in Wales, another lead author.
Treatments for schizophrenia have not advanced in more than 50 years, since the discovery of drugs that reduce the activity of the chemical messenger dopamine. A leading theory has therefore focused on overactive dopamine signaling. Sure enough, one of the identified regions contains a gene that produces the type of dopamine receptor that is blocked by antipsychotic drugs.
Another of the brain's chemicals, glutamate, has also received attention, but drugs that target it have not fared well in clinical trials. The new study implicated several glutamate-related genes. “This is important confirmatory evidence that glutamate is relevant to schizophrenia,” O'Donovan says. “Exactly how is another question.” Past drugs may have failed because, for instance, they targeted the wrong kind of glutamate receptor; the genetic results will help drug developers focus their efforts.
The meaning of some of the other findings is less clear. Immune system genes were implicated, as were genes previously associated with smoking. These findings do not necessarily mean that schizophrenia is related to immunity or that smoking causes schizophrenia. The area of the genome related to immunity contains hundreds of genes, some of which affect other aspects of biology. Genes can also perform distinct roles in various tissues. “A lot of immune system proteins probably have different functions in the brain,” O'Donovan says. The link with smoking is similarly opaque. For instance, one genetic variant might both predispose people to smoking and increase the risk of schizophrenia, without one causing the other.
An important overall conclusion is that schizophrenia is a complex trait like any other, but its complexity does not mean it will remain mysterious. Past GWAS research has led to breakthroughs for other health conditions with tangled genetic and environmental roots, such as diabetes and Crohn's disease, and experts believe that this study will do the same for schizophrenia. “That there are lots of small, common genetic effects, scattered across the genome, is itself an important finding,” Neale says. “There are many different biological processes involved.”
