Intensive DNA search yields 10 genes tied directly to schizophrenia

HOUSTON, TEXAS—Schizophrenia tends to run in families, which suggests it’s largely inherited. But a long-running search for genes underlying this severe psychiatric condition has yielded only indirect clues. Now, by scouring the DNA of tens of thousands of people, gene hunters have for the first time nabbed a handful of rare genes that, when mutated, appear to be direct contributors to the disease—and may shed light on what goes awry in a schizophrenia patient’s brain.

“These are concrete genes with mutations with a clear molecular mechanism,” says Mark Daly of the Broad Institute in Cambridge, Massachusetts, and the University of Helsinki, who is principal investigator for a consortium that presented the work last week at the annual meeting of the American Society of Human Genetics (ASHG) here.

“It was a fabulous talk,” says Jennifer Mulle of Emory University in Atlanta, who studies the genetics of psychiatric disorders. “We don’t understand anything about the biological pathways [in schizophrenia]. Now, these genes give us an avenue.”

People with schizophrenia, which afflicts about 0.7% of the U.S. population, have a distorted sense of reality and confused thinking; they may have hallucinations and delusions. Some patients share similar genetic abnormalities, such as missing specific chunks of DNA, but how those gaps may contribute to disease isn’t known.

Taking a different approach, human geneticists have for years examined DNA markers spread along the genome to find the ones more common in people with schizophrenia than in those without the disease. By now these genomewide association studies (GWASs) have found more than 270 markers in stretches of DNA that regulate genes. But tying a marker to a specific gene and untangling the gene’s role in disease is slow, painstaking work.

Hoping to move faster, a global consortium called Schizophrenia Exome Sequencing Meta-Analysis 2 years ago began to gather patients’ exomes, or the DNA that codes for proteins, rather than regulating genes. The consortium now has exomes for 24,000 people with schizophrenia and 97,000 without the disorder, and so have achieved the statistical power they need: They have now found 10 genes with ultrarare disabling variants that promote schizophrenia. If one of a person’s two copies of any of these genes are the disabled type, their risk of developing schizophrenia increases four to 50 times, depending on the gene, reported Broad Institute postdoctoral researcher Tarjinder Singh in an ASHG plenary session on 15 October. That very high risk suggests the genes—only one of which had been identified before—play a large, direct role in some cases of the disease.

Two genes, GRIN2A and SP4, overlap with GWAS markers. This suggests that even though fewer than one in 10,000 people carry the high-risk mutations, variants of the same genes that boost schizophrenia risk by smaller amounts may be more common. Importantly, GRIN2A and a third gene among the 10 called GRIA3 encode for brain receptors for the neurotransmitter glutamate. Some researchers have long suspected that the glutamate pathway is involved in schizophrenia, in part because two drugs that block these receptors, PCP and ketamine, can trigger schizophrenialike symptoms. Now, they have genetic confirmation and a new impetus to develop drugs that target the glutamate pathway, Mulle says.

Other genes among the 10 spotted by the exome work didn’t overlap with earlier GWAS markers, but are involved in synaptic and neuronal processes, and may reveal novel details of the disease’s biology, Singh says. And another 30 or so genes with more tentative links to schizophrenia overlapped with several genes implicated in autism spectrum disorder, suggesting a link with that disease.