Two major genetic studies involving many hundreds of thousands of participants have identified hundreds of genome regions that may harbor genes linked to schizophrenia. One of the studies identified multiple genes with rare mutations that appear to be associated with the disorder.
In what they call a landmark exome sequencing study that involved 121,000 people, the international SCHEMA (SCHizophrenia Exome Meta-Analysis) consortium, 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. The second reported work, a genome-wide association study (GWAS) in a larger but overlapping group of 320,400 people, was conducted by the Psychiatric Genomics Consortium (PGC)—which including the same Broad researchers—and brings to 287 the number of regions of the genome associated with schizophrenia risk, including loci containing genes identified by SCHEMA.
The two studies appear alongside each other in Nature. Together, they underscore 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,” said Tarjinder Singh, PhD, a postdoctoral fellow in the Stanley Center for Psychiatric Research at the Broad Institute. “Unlike cardiovascular disease or cancer, we have had very few biological clues to disease mechanisms. As a result, we have lacked the necessary insights for development of much needed new treatments. Instead we have been iterating on the antipsychotic drugs serendipitously discovered more than 70 years ago.” Singh, who is also in the Analytic and Translational Genetics Unit (ATGU) at Massachusetts General Hospital, is first, and co-corresponding author of the SCHEMA study, which is titled “Rare coding variants in the genes confer substantial risk for schizophrenia,” and a collaborator on the PGC study, which is titled, “Mapping genomic loci implicates genes and synaptic biology in schizophrenia.”
According to Singh, these two studies were possible because the necessary pieces were finally in place. “The genomic technologies, the sequencing infrastructure, the computational tools needed to understand the data they produce, have advanced dramatically in the last two decades,” he said. “The most important piece was the global commitment on the part of PGC and SCHEMA members to share samples and data across institutions and nations to achieve the numbers of people needed to bring these rare mutations to light.”
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 disorder has a heritability of 60–80%, the PGC authors noted, and “Much of the between-individual variation in risk is genetic, and involves large numbers of common alleles, rare copy number variants (CNVs) and rare coding variants.” And while there is a need for new therapeutic targets, this process is :impeded by our limited understanding of pathophysiology.” The SCHEMA authors concurred, “The lack of progress in therapeutic development is in part a consequence of the limited understanding of the molecular aetiology of psychiatric disorder,” the SCHEMA authors noted.
The SCHEMA and PGC findings result from a decade-long push led by researchers at the Stanley Center and nearly four dozen other institutions around the world. Both projects aim to gather and compare DNA from large numbers of people with and without schizophrenia. By working together, investigators across the PGC have built a dataset that now includes more than 320,400 people from collections across the world, including people of European, Finnish, African American, LatinX, East Asian, and Ashkenazi Jewish descent. The SCHEMA cohort comprises a subset of that, representing more than 121,000 people.
The two groups have followed complementary paths in their study of schizophrenia genetics. Since 2009, the PGC team has conducted increasingly larger genome-wide association studies cataloging single nucleotide polymorphisms (SNPs) that contribute to schizophrenia risk. For their newly reported study, the PGC said, “We have performed the largest—to our knowledge—GWAS of schizophrenia to date and in doing so, have identified a substantial increase in the number of associated loci”
The SCHEMA (SCHizophrenia Exome Meta-Analysis) Consortium—which came together in 2017—focuses on the exome, the nearly 2% of the genome that encodes proteins. Specifically, the SCHEMA Consortium looked for variants that would either knock out or markedly alter a gene’s ability to produce functioning proteins.
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 Benjamin Neale, PhD, another co-corresponding author on the SCHEMA study, a PGC collaborator, an institute member and director of genetics in the Stanley Center, co-director of the institute’s Program in Medical and Population Genetics, and faculty of the Mass General ATGU. “But if you have one of these mutations, it becomes a 10, 20, even 50 percent chance.”
Reporting in their newly released paper, the SCHEMA authors noted, “In one of the largest exome sequencing studies thus far, we identify genes in which disruptive coding variants confer substantial risk for schizophrenia at exome-wide significance. This effort required the reprocessing of a decade of sequence data, harmonization of variant calling and quality control, inclusion of external controls and integration of PTV [protein truncating variants], damaging missense and de novo variants. Global collaborative efforts such as these provide a template for tackling the genetic contributions in other complex diseases.”
Neale further commented, “Identifying these 10 genes is a watershed moment in schizophrenia research because each one of them provides a solid foundation for launching biological inquiry. By sequencing the DNA of thousands of people, we are starting to see exactly which genes matter. These discoveries are the starting point for developing new therapies that treat the root cause of this devastating condition.”
“We’ve tried for years and years to gain this kind of traction on the biology of schizophrenia,” said Broad core institute member and Stanley Center director Steven Hyman, PhD. “Realistically, it will take yet more years to translate these results into biomarkers and treatments that will make a difference in the lives of people who are suffering with this devastating illness. But it is highly motivating to have a compelling path forward.”
“There’s 10 years worth of data represented in these studies,” added Sinéad Chapman, PhD, the director, global genetics project management in the Stanley Center who, along with team members Christine Stevens, Caroline Cusick, and many others, spent hundreds of hours ensuring that the samples and data from the SCHEMA collaborators were properly processed and tracked for these analyses. “It was quite a manual process, as there isn’t one magic system to connect all the samples and data and all of their related regulatory and clinical information.”
The SCHEMA study findings also hinted at an additional 22 genes that also likely influence schizophrenia risk, and which may prove significant after further study. Data from the SCHEMA study are available at schema.broadinstitute.org.
Together, the identified genes point to dysfunction at the synapse—where neurons connect and communicate with each other—as a possible cause of schizophrenia. This idea first emerged several years ago, thanks in part to a 2016 study by researchers at the Broad’s Stanley Center, Harvard Medical School, and Boston Children’s Hospital. In that study, investigators described for the first time how variations in a single gene—complement component 4, or C4—raises schizophrenia risk by triggering excessive “pruning” of synapses.
Insights into two of the 10 genes from the SCHEMA study, GRIN2A and GRIA3, further implicate the synapse as a key part of schizophrenia’s mechanistic roots. These two genes encode portions of the glutamate receptor, a cellular antenna found at the synapse that allows neurons to receive chemical signals from neighboring neurons. Pharmacological studies have previously suggested that glutamate signaling may be involved in schizophrenia, but the SCHEMA study provides the first solid genetic evidence of this. Additionally, GRIN2A activity in the brain peaks during adolescence, around the time people suffering schizophrenia begin to experience symptoms.
“The genome-wide analyses recapitulated known biological processes and reaffirmed that schizophrenia risk genes are involved in the postsynaptic density and broader synaptic function and are enriched in expression in neuronal tissues,” the SCHEMA authors commented in their report. “The association of PTVs in the NMDA receptor subunit GRIN2A with schizophrenia risk provides genetic support for the dysregulation of glutamatergic signalling as a possible mechanism of disease.”
Most of the SCHEMA genes had never before been associated with a brain disorder or neuron-specific functions. One gene (SETD1A) is involved in transcriptional regulation. Another (CUL1) helps the cell recycle old or unneeded proteins, while yet another (XPO7) helps chaperone molecules out of the cell’s nucleus. Yet in the SCHEMA analysis, PTVs in these genes drive a 20- to 52-fold increase in schizophrenia risk.
“We don’t yet have a well-developed framework for understanding how these genes might play a role in schizophrenia,” said SCHEMA co-corresponding author and PGC collaborator Mark Daly, PhD, who is also an institute member in the Stanley Center, Mass General ATGU faculty, and director of the Institute for Molecular Medicine, Finland. “These genes will ultimately lead to some new insights, but are going to require a lot of experimental follow-up to see where they might fit in the puzzle.”
The PGC team, led by scientists at Cardiff University, examined common genetic variations in 76,755 people with schizophrenia and 243,649 without the disorder, finding 287 genome loci as having some involvement in schizophrenia risk, an increase of 94 loci since the last PGC analysis was released in 2019. With further analysis the PGC teams identified 120 genes that potentially increase risk for schizophrenia. Several of these genes were also identified in the SCHEMA study.
Furthermore, the PGC results indicated that genetic risk for schizophrenia is seen in genes concentrated in brain cells called neurons, but not in any other tissue or cell type, suggesting it is the biological role of these cells that is crucial in schizophrenia.
“Previous research has shown associations between schizophrenia and many anonymous DNA sequences, but rarely has it been possible to link the findings to specific genes,” said co-lead author Professor Michael O’Donovan, PhD, from the Division of Psychological Medicine and Clinical Neurosciences at Cardiff University.
“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.”
As well as being the largest study of its kind, the PGC researcher included more than 7,000 people with either African American or Latino ancestries in what the team says is a small step towards making sure advances that come from genetic studies can benefit people beyond those of European ancestries.
Although there are large numbers of genetic variants involved in schizophrenia, the study showed they are concentrated in genes expressed in neurons, pointing to these cells as the most important site of pathology. The findings also suggested that abnormal neuron function in schizophrenia affects many brain areas, which could explain its diverse symptoms, which can include hallucinations, delusions and problems with thinking clearly. “We show that genes we prioritize within associated loci by fine-mapping are enriched for those with an increased burden of rare deleterious mutations in schizophrenia, and identify GRIN2A, SP4, STAG1 and FAM120A as specific genes in which the convergence of rare and common variant associations strongly supports their pathogenic role in the disorder,” the PGC team wrote in the published paper. “Enrichment of common variant associations was restricted to genes that are expressed in neurons of the central nervous system—both excitatory and inhibitory—and that have functions in fundamental biological processes related to neuronal function. This indicates that neurons are the most important site of pathology in schizophrenia.”
Professor James Walters, co-lead author on the Cardiff-led paper and Director of the MRC Centre for Neuropsychiatric Genetics and Genomics at Cardiff University, said: “Whilst people with schizophrenia can recover, many do not respond well to treatments, experience long-term problems with their mental and physical health, as well as impacts on relationships, education and work We hope the findings in this, and the companion studies, can be used to advance our understanding of the disorder and facilitate the development of radically new treatments. However, those processes are often not straightforward, and a lot of work by other neuroscientists is needed to translate the genetic findings into a detailed understanding of disease mechanisms.”
The Psychiatric Genomics Consortium is funded by the National Institute of Mental Health (NIMH), and work in Cardiff was additionally supported by the Medical Research Council. Joshua Gordon, MD Director of NIMH, said, “These results, achieved through a global collaboration unprecedented in scope, mark 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 serious mental illness.”
The PGC study demonstrated the importance and power of large samples in genetic studies to gain insights into psychiatric disorders. The team are now seeking to recruit more research participants and build larger, more diverse datasets to further advance our understanding of schizophrenia.
The nature and effect of the variants detected by PGC differed in some ways from the SCHEMA findings, the Broad Institute noted. For instance, the damaging protein-coding GRIN2A mutations SCHEMA identified are extremely rare and raise schizophrenia risk 24-fold. The variants found in the PGC study are far more common and change GRIN2A expression, increasing risk by only 1.06-fold.
However, the fact that both studies’ findings converge 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.
Most of the SCHEMA genes had never before been associated with a brain disorder or neuron-specific functions. One gene (SETD1A) is involved in transcriptional regulation. Another (<CUL1) helps the cell recycle old or unneeded proteins, while yet another (XPO7) helps chaperone molecules out of the cell’s nucleus. Yet in the SCHEMA analysis, PTVs in these genes drive a 20- to 52-fold increase in schizophrenia risk.
“We don’t yet have a well-developed framework for understanding how these genes might play a role in schizophrenia,” said SCHEMA co-corresponding author and PGC collaborator Mark Daly, PhD, who is also an institute member in the Stanley Center, Mass General ATGU faculty, and director of the Institute for Molecular Medicine, Finland. “These genes will ultimately lead to some new insights, but are going to require a lot of experimental follow-up to see where they might fit in the puzzle.”
The PGC team, led by scientists at Cardiff University, examined common genetic variations in 76,755 people with schizophrenia and 243,649 without the disorder, finding 287 genome loci as having some involvement in schizophrenia risk, an increase of 94 loci since the last PGC analysis was released in 2019. With further analysis the PGC teams identified 120 genes that potentially increase risk for schizophrenia. Several of these genes were also identified in the SCHEMA study.
Furthermore, the PGC results indicated that genetic risk for schizophrenia is seen in genes concentrated in brain cells called neurons, but not in any other tissue or cell type, suggesting it is the biological role of these cells that is crucial in schizophrenia.
“Previous research has shown associations between schizophrenia and many anonymous DNA sequences, but rarely has it been possible to link the findings to specific genes,” said co-lead author Professor Michael O’Donovan, PhD, from the Division of Psychological Medicine and Clinical Neurosciences at Cardiff University.
“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.”
As well as being the largest study of its kind, the PGC researcher included more than 7,000 people with either African American or Latino ancestries in what the team says is a small step towards making sure advances that come from genetic studies can benefit people beyond those of European ancestries.
Although there are large numbers of genetic variants involved in schizophrenia, the study showed they are concentrated in genes expressed in neurons, pointing to these cells as the most important site of pathology. The findings also suggested that abnormal neuron function in schizophrenia affects many brain areas, which could explain its diverse symptoms, which can include hallucinations, delusions and problems with thinking clearly. “We show that genes we prioritize within associated loci by fine-mapping are enriched for those with an increased burden of rare deleterious mutations in schizophrenia, and identify GRIN2A, SP4, STAG1 and FAM120A as specific genes in which the convergence of rare and common variant associations strongly supports their pathogenic role in the disorder,” the PGC team wrote in the published paper. “Enrichment of common variant associations was restricted to genes that are expressed in neurons of the central nervous system—both excitatory and inhibitory—and that have functions in fundamental biological processes related to neuronal function. This indicates that neurons are the most important site of pathology in schizophrenia.”
Professor James Walters, co-lead author on the Cardiff-led paper and Director of the MRC Centre for Neuropsychiatric Genetics and Genomics at Cardiff University, said: “Whilst people with schizophrenia can recover, many do not respond well to treatments, experience long-term problems with their mental and physical health, as well as impacts on relationships, education and work We hope the findings in this, and the companion studies, can be used to advance our understanding of the disorder and facilitate the development of radically new treatments. However, those processes are often not straightforward, and a lot of work by other neuroscientists is needed to translate the genetic findings into a detailed understanding of disease mechanisms.”
The Psychiatric Genomics Consortium is funded by the National Institute of Mental Health (NIMH), and work in Cardiff was additionally supported by the Medical Research Council. Joshua Gordon, MD Director of NIMH, said, “These results, achieved through a global collaboration unprecedented in scope, mark 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 serious mental illness.”
The PGC study demonstrated the importance and power of large samples in genetic studies to gain insights into psychiatric disorders. The team are now seeking to recruit more research participants and build larger, more diverse datasets to further advance our understanding of schizophrenia.
The nature and effect of the variants detected by PGC differed in some ways from the SCHEMA findings, the Broad Institute noted. For instance, the damaging protein-coding GRIN2A mutations SCHEMA identified are extremely rare and raise schizophrenia risk 24-fold. The variants found in the PGC study are far more common and change GRIN2A expression, increasing risk by only 1.06-fold.
However, the fact that both studies’ findings converge 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.
“Our hope was that we would end up with some amount of overlap in the stories that the common and rare variant associations were telling us,” said Neale. “And we see overlap pointing to a relationship between synaptic biology and schizophrenia risk.” Although, as the PGC researchers noted in their paper, “Disrupted neuronal function in schizophrenia is unlikely to be restricted to the synapse, but the concentration of associations in genes with pre- and postsynaptic locations, and with functions related to synaptic organization, differentiation and transmission, point to the pathophysiological importance of these neuronal compartments and their attendant functions.”
The SCHEMA data also shed light on how psychiatric and neurodevelopmental disorders more broadly can share genetic risk. For instance, several SCHEMA genes, including GRIN2A, have previously been implicated with neurodevelopmental conditions such as epilepsy, developmental delay, and intellectual disability.
But by comparing their data from that of other large-scale studies, the SCHEMA team noted that the overlaps they saw were driven by different kinds of mutations: PTVs for schizophrenia, missense mutations (which can lead to amino acid swaps that modify a protein’s activity) for the neurodevelopmental conditions.
“We see that a spectrum of consequences can arise from different kinds of mutation in the same genes,” Neale noted. “We have a lot more to do and a lot more to learn about what these genes do, what variations in these genes do, and what the biological consequences of genetic variation really are writ large.”
“This point is critical for gaining insight into how genetics works across brain disorders,” Daly added. “We need to make sure that we don’t take a siloed view of these data, and instead remain open to learning what these genetics has to teach us across phenotypes.”
“These first 10 genes are really only the beginning of genetic discovery,” Neale said. “There is pretty clear evidence that there are many more genes to discover using the same kind of approach. But we fundamentally need bigger sample sizes to be able to reveal those additional genes.
“But, if you have more pieces of the puzzle,” he continued, “it might be a little bit easier to fit them together and come into a slightly more coherent mechanistic view of schizophrenia, and how we might start to approach those processes with the hope of improving patient’s lives.”
“The biological complexity of schizophrenia is truly daunting, but this combination of rare protein altering variants from exome sequencing and common variants from GWAS have put us on our way to understanding the roots of that complexity,” said Hyman. “In these results, we may be seeing how synaptic abnormalities or losses begin in schizophrenia, giving us openings to diagnosing and treating people much earlier than we can today.”
“With schizophrenia, like with other complex disorders, I think we will ultimately find that many processes are involved in risk or protection,” Daly added. “Understanding that may turn out to be one of the most complex undertakings in genetics and biology.”
And as the SCHEMA investigators concluded in their paper, “The success of common variant association studies, and now exome sequencing, suggests concrete progress towards understanding the causes of human complex traits and diseases and provides a clear roadmap for understanding the genetic architecture of schizophrenia.”
