Schizophrenia is a serious psychiatric disorder that starts in late adolescence or early adulthood and at any one time affects around one in 300 people worldwide, according to the World Health Organisation.
The study by an international consortium called SCHEMA, led by researchers at the Broad Institute of MIT and Harvard identified extremely rare protein-disrupting mutations in 10 genes that strongly increase an individual's risk of developing schizophrenia – in one instance, by more than 20-fold.
A second, complementary study in a larger but overlapping group of 320,400 people, conducted by the Psychiatric Genomics Consortium (PGC) led by scientists at Cardiff University, found a much larger number of genetic links to schizophrenia than ever before, in 287 different regions of the genome — the human body's DNA blueprint. This includes the genes identified in SCHEMA study.
These studies, appearing together in the journal Nature, underscores an emerging view of schizophrenia as a breakdown in communication at the synapse (the junction between neurons), and illustrate how different kinds of genetic variation affecting the same genes can influence the risk for different psychiatric and neurodevelopmental disorders.
"Psychiatric disorders have been a black box for a very long time. Unlike cardiovascular disease or cancer, we have had very few biological clues to disease mechanisms," said Tarjinder Singh, a postdoctoral fellow in the Stanley Center for Psychiatric Research at the Broad Institute.
But, several previous research showed associations between schizophrenia and many anonymous DNA sequences. However, it has been rarely possible to link the findings to specific genes.
"The present study not only vastly increased the number of those associations, but we have now been able to link many of them to specific genes, a necessary step in what remains a difficult journey towards understanding the causes of this disorder and identifying new treatments," said Professor Michael O'Donovan, from the Division of Psychological Medicine and Clinical Neurosciences at Cardiff University.
By sequencing whole exomes from 24,248 people with schizophrenia and 97,322 without, the SCHEMA team identified ultra-rare variants in 10 genes that dramatically increased a person's risk of developing schizophrenia. These variants, called PTVs for "protein-truncating variants," prevent cells from producing a gene's full-length functional protein.
"In general, any given person has a roughly one percent chance of developing schizophrenia in their lifetime," said Neale. "But if you have one of these mutations, it becomes a 10, 20, even 50 percent chance."
Their findings also hint at an additional 22 genes that also likely influence schizophrenia risk, which may prove significant after further study.
Together, these genes point to dysfunction at the synapse — where neurons connect and communicate with each other — as a possible cause of schizophrenia.
Separately, the PGC team examined common genetic variations in 76,755 people with schizophrenia and 243,649 without, finding 287 regions of the genome (or loci) as having some involvement in schizophrenia risk. With further analysis, they identified 120 genes that potentially increase the risk for schizophrenia, several of which were also identified in the SCHEMA study.
The PGC team also found that the genomic regions they implicated are largely active only in neurons, only in the brain, and affect mechanisms that directly impact neuron function, such as synaptic structure and organization.
However, the fact that both studies' findings converge on similar groups of genes and similar biological mechanisms suggests that genetic discoveries are beginning to home in on core aspects of schizophrenia biology, and are close to broader insights into the mechanisms underlying schizophrenia progression. (AA/IANS)