Biggest study so far implicates synaptic genes in schizophrenia

12 April 2022

An international consortium analysed DNA from more than 300,000 people with and without the disorder. The SYNGO consortium, coordinated by CNCR, performed the analyses of synaptic genes. The study is published in Nature on April 11th

The largest ever genetic study of schizophrenia has identified considerable numbers of genes that could play important roles in the psychiatric disorder. A team of hundreds of researchers across 45 countries analysed DNA from 76,755 people with schizophrenia and 243,649 without it to better understand the genes and biological processes underpinning the condition. The study was coordinated by the Psychiatric Genomics Consortium and found a much larger number of genetic links to schizophrenia than ever before, in 287 different regions of the human genome. Risk for schizophrenia was detected in genes primarily expressed in neurons, but not in any other tissue or cell type. The current study provides a substantial improvement in defining the genetic basis of schizophrenia and marks an important step forward in our understanding of the origins of schizophrenia. The findings will allow researchers to focus on specific brain pathways in the ongoing hunt for novel therapies for this mental illness.

The SYNGO consortium, coordinated by Frank Koopmans, Loek van der Kallen, Guus Smit and Matthijs Verhage, was responsible for the functional annotation of synaptic genes among the observed genetic links. SYNGO detected 15 new links to pre- and postsynaptic genes. These new links open new directions for research to understand how synaptic deficits contribute to the risk for schizophrenia.

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 Organization. The present study not only vastly increased the number of links between genetic variation in the population and the disease, but also links to specific genes, a necessary step in what remains a difficult journey towards understanding the causes of this disorder and identifying new treatments.

“The SYNGO consortium is really proud to contribute to this global collaboration unprecedented in scope and apply its domain expertise on synapse biology for the understanding of schizophrenia” says Matthijs Verhage, professor of Functional Genomics at CNCR (VU/AUMC) and co-coordinator of SYNGO. “The contribution of SynGO to the analyses provides a path to new research into synaptic dysfunction in SCZ”, says Guus Smit, co-coordinator of SynGO and director of CNCR.

Although there are large numbers of genetic variants involved in schizophrenia, the study showed they are concentrated in genes expressed in neurons and their contact sites, the synapses. This clearly implicates these as the most important site of pathology. The findings also suggest abnormal neuron function in schizophrenia affects many brain areas, which could explain its diversity in symptoms, which can include hallucinations, delusions and problems with thinking clearly.

The SYNGO consortium is funded by The Stanley Center of the Broad Institute of MIT, Cambridge, MT, USA; The Simons Foundation for Autism Research and the Vrije Universiteit and Amsterdam University Medical Center.

The paper can be found here