Genome-wide association studies (GWAS) seek to understand how very small changes in the human genome can contribute to disease risk. Advances in genomic sequencing and computational technologies have made it possible to include huge numbers of people in these investigations. That effort has revealed many new genetic links to disease, and has taught us more about the biological basis of some disorders. New GWAS studies have aimed to learn more about the genetics and biology of a mysterious disease, schizophrenia; one included data from over 121,000 people from around the world, which was collected by the SCHEMA consortium, and another, data from 320,400 people from the Psychiatric Genomics Consortium (PGC). Scientists have identified novel mutations in many genes that significantly increase the likelihood of a schizophrenia diagnosis.
Reporting in Nature, the two studies have suggested that schizophrenia is a result of a breakdown in synapses, the junctions were neurons meet and send signals to one another. The studies indicated that errors in different genes can ultimately lead to similar dysfunctions that impact the risk of psychiatric and neurodevelopmental disorders.
The researchers noted that there are few effective treatments for psychiatric disorders, and these studies can reveal new drug targets because they show how the disease can arise, and "exactly which genes matter," said a co-corresponding author of the SCHEMA study, Benjamin Neale, the director of genetics at the Stanley Center for Psychiatric Research at the Broad Institute, among other appointments.
"We've tried for years and years to gain this kind of traction on the biology of schizophrenia," said Stanley Center director Steven Hyman. "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."
This work has taken decades and the efforts of many people and institutions. The genetic data that was gathered, however, represents African American, Ashkenazi Jewish, East Asian, European, Latinx, and other populations. Scientiists have been improving genetic studies by including people of diverse backgrounds; such studies are more likely to bring us an accurate picture of disease, and greater equity in medicine.
The SCHEMA (SCHizophrenia Exome Meta-Analysis) Consortium was established in 2017, and has looked for schizophrenia-linked genetic variations in the part of the genome that codes for protein, called the exome. The exomes of 24,248 people diagnosed with schizophrenia and 97,322 that had not been were analyzed. The researchers were looking for variations in genes that affected a gene's ability to generate a protein of the correct length, so-called protein truncating variants (PTVs).
"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."
In the SCHEMA study, ten schizophrenia-associated genes were found along with 22 candidate genes that probably influence schizophrenia risk, but need further confirmation.
Previous work has suggested that schizophrenia risk may increase when synapses are reduced, or pruned, too much. The SCHEMA study seems to confirm that hypothesis, and also revealed other schizophrenia-linked genes including GRIN2A and GRIA3, which encode for parts of the glutamate receptor, found on neurons. Glutamate has previously been implicated in schizophrenia. GRIN2A mutations have been associated with other neurodevelopment disorders as well. PTVs in the genes highlighted by this study were responsible for increasing the risk of schizophrenia by 20 to 52 times.
In the PGC analysis, 287 genetic regions were found to be related to schizophrenia risk, including 120 genes. Several of those genes were also revealed by SCHEMA. In the PGC study, the researchers noted that the regions that were identified were primarily active in neurons in the brain, and are mostly related to neuronal function.
"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."
SCHEMA also determined that PTVs are more likely to lead to schizophrenia, while missense mutations are related to neurodevelopmental conditions.
"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," said Hyman.
Sources: Broad Institute of MIT and Harvard, SCHEMA, Nature
