Summary: A new multi-center study led by researchers at the Icahn School of Medicine at Mount Sinai identifies two previously unreported genes linked to schizophrenia and implicates a third gene as carrying risk for both schizophrenia and autism.
Source: Mount Sinai Health System
Researchers have discovered two novel genes associated with schizophrenia and have newly implicated a third gene as contributing risk for both schizophrenia and autism.
The study, led by the Icahn School of Medicine at Mount Sinai and conducted across multiple international centers, also shows that the risk from rare damaging variants in these genes is conserved across different ancestral groups. The findings, published online in the March 13 issue of Nature Genetics, may inform future therapeutic development.
Schizophrenia is one of the most serious psychiatric disorders, affecting roughly 1 in 100 people worldwide. It alters thinking, emotion, and behavior and can cause symptoms that make it difficult for patients to distinguish what is real. The disorder is highly heterogeneous and arises from many interacting causes, including both common and rare genetic variants.
To identify genes with rare damaging variants that increase schizophrenia risk, investigators compared protein-coding gene sequences from people diagnosed with schizophrenia to those of healthy controls. The meta-analysis combined existing datasets totaling up to 35,828 cases and 107,877 controls, making this one of the largest examinations of rare variant burden in schizophrenia across diverse populations, including substantial representation of individuals of African ancestry.
From that analysis, the team identified two genes not previously tied to schizophrenia: SRRM2 and AKAP11. Both genes carry rare protein-truncating or otherwise damaging variants that are enriched among people with schizophrenia compared with controls. In addition, the study identified the gene PCLO as having a shared role in risk for schizophrenia and autism, reinforcing the idea that some genetic factors influence multiple neurodevelopmental and psychiatric conditions.
Importantly, the research found that the elevated risk associated with rare damaging variants in evolutionarily constrained genes appears consistent across ancestral groups. That cross-population conservation suggests that discoveries made in one population can be relevant more broadly and highlights the value of including diverse cohorts in genetic studies. The work builds on a prior study that had identified 10 schizophrenia risk genes but had been carried out primarily in populations of European ancestry.
Lead author Dongjing Liu, PhD, formerly a postdoctoral researcher in Alexander W. Charney, MD, PhD’s laboratory at Icahn Mount Sinai, noted that concentrating on a targeted set of genes enabled the team to detect rare damaging variants that could point toward new drug targets for schizophrenia. Co-senior corresponding author Alexander W. Charney emphasized the clinical implications of the PCLO finding: the same gene can appear to produce different clinical outcomes in the same family, with one relative showing autism and another schizophrenia. That pleiotropy—where a single gene influences multiple, distinct conditions—may help explain overlapping biology across brain disorders and could inform future treatment strategies.
The authors caution that these genetic discoveries do not explain schizophrenia for every individual. Schizophrenia is multifactorial; many people with the disorder do not carry rare damaging variants in the genes identified here, and environmental and other genetic factors also contribute to disease risk.
Next steps for the researchers include assessing whether variation in these genes maps to particular clinical features or symptom profiles of schizophrenia and evaluating whether existing or novel compounds could modulate the biological pathways affected by these genes. Such translational work will be needed to determine clinical utility and to move from genetic discovery toward targeted interventions.
Co-senior corresponding author Laura M. Huckins, PhD, formerly at Icahn Mount Sinai and now an Associate Professor of Psychiatry at Yale School of Medicine, paid tribute to the study’s conceptual roots in the work of their late mentor Pamela Sklar, MD, PhD. The team also acknowledged the large international collaboration that made the analysis possible and expressed gratitude to the participants and partner groups whose contributions enabled this research.
The peer-reviewed paper is titled, “Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations.”
About this genetics and schizophrenia research news
Author: Karin Eskenazi
Source: Mount Sinai Health System
Contact: Karin Eskenazi – Mount Sinai Health System
Image: The image is credited to Neuroscience News and was created using DALL‑E 2 AI technology
Original Research: The findings appear in Nature Genetics