Extensive DNA research reveals 10 genes directly related to schizophrenia

Schizophrenia is a serious psychiatric illness that involves a distorted sense of reality, including altered states of consciousness and hallucinations. The genetic character of the disease has long been evident, as cases tend to be repeated within the same family. This suggests that it is a largely hereditary disease. Previously, a large study to determine which underlying genes are involved has yielded only indirect cues. But now, by exploring the DNA of tens of thousands of people, researchers have for the first time identified several rare genes that, once mutated, seem to contribute directly to schizophrenia. This discovery could shed light on the exact impact of the disease on brain function.

These are concrete genes with mutations involving a clear molecular mechanism ," says Mark Daly of Broad Institute in Cambridge, Mass., And University of Helsinki, lead investigator of a consortium that presented the work last week. at the annual meeting of the American Society of Human Genetics (ASHG).

" It was a fabulous speech ," says Jennifer Mulle of Emory University in Atlanta, who studies the genetics of psychiatric disorders. " We do not understand much about the biological pathways of schizophrenia. Now, these genes give us a track  . "

People with schizophrenia, a disease that affects about 0.7% of the world's population (including 600,000 individuals in France), have a distorted sense of reality and a confused thought. They can have hallucinations and delusions. Some patients share similar genetic abnormalities, such as missing specific DNA fragments, but it remains unclear how these deficiencies could contribute to the disease.

More than 270 genetic markers potentially involved

Geneticists have been examining genetic markers along the genome for years to find those that are more common in individuals with schizophrenia, compared to those who do not. To date, these Genome Wide Association Studies (GWAS) have revealed more than 270 markers in DNA segments that regulate genes. But linking a marker to a specific gene and identifying its role in the disease is slow and laborious work.

In the hope of progressing faster, a global consortium called Meta- Schizophrenia Exome Sequencing ( Schizophrenia exome meta-analysis consortium ) was started 2 years ago. The project aims to collect patient exomes (ie DNA encoding proteins) rather than regulatory genes. So far, the exomes of 24'000 people with schizophrenia and 97'000 other subjects without disorder have been collected. Thus, the necessary statistical power has been achieved.

A 4- to 50-fold increase in the risk of developing schizophrenia

After analyzes, the researchers were able to identify 10 genes with very rare disabling variants that favor schizophrenia. If one of the two copies of one of these genes in an individual is of the dysfunctional type, the risk of developing schizophrenia increases from 4 to 50 times , depending on the gene in question, explains Tarjinder Singh, a postdoctoral researcher at the Broad Institute. , at a plenary session of the ASHG held on October 15th. This very high risk suggests that genes - only one of which was previously identified - play an important direct role in some cases of the disease.

Two specific genes, GRIN2A and SP4 , overlap with GWAS markers. This suggests that although fewer than one in 10,000 people carry high-risk mutations, variants of the same genes that slightly increase the risk of schizophrenia may be more common. It is important to note that GRIN2A, as well as a third of the 10 genes called GRIA3, encode important brain neurotransmitter glutamate receptors.

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 symptoms similar to those of schizophrenia. Now, they have genetic confirmation and new impetus to develop drugs that target the glutamate pathway, says Mulle.

A potential link with autism

Other genes among the 10 identified in the exome study do not overlap with previous GWAS markers, but are involved in synaptic and neuronal processes and may reveal new details of the biology of the sickness. In addition, about 30 genes with more temporary links to schizophrenia overlap with several genes involved in autism spectrum disorder, suggesting a link with this disorder.

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