Summary: New research links schizophrenia risk to somatic copy-number variants—mutations that arise after conception rather than being inherited—highlighting recurrent disruptions in the genes NRXN1 and ABCB11.
A large analysis of genotype-marker data from more than 20,000 blood samples found that somatic copy-number variants (sCNVs) that occur early in development are more frequent in people with schizophrenia than in controls. The team identified two genes, NRXN1 and ABCB11, whose recurrent disruptions were associated with schizophrenia cases, suggesting an underappreciated role for acquired mutations in the disorder’s genetic architecture.
NRXN1, a gene essential for synaptic signaling across the brain, has been previously linked to schizophrenia through inherited mutations. This study is among the first to show that non-inherited, somatic NRXN1 deletions—likely arising during early embryonic development—are also associated with schizophrenia. ABCB11, a gene best known for encoding a liver transporter, unexpectedly emerged as recurrently disrupted in a subset of treatment-resistant schizophrenia cases and appears to be expressed in specific dopamine-producing neurons relevant to antipsychotic response.
Key Facts:
- Somatic copy-number variants, which occur after fertilization and are present in only some cells, are associated with increased schizophrenia risk.
- Recurrent disruptions of NRXN1 and ABCB11 were detected in schizophrenia cases, implicating these genes when altered during early development.
- The finding that ABCB11 disruptions are linked to treatment-resistant schizophrenia highlights potential connections between somatic mutations and drug response mechanisms.
Source: Cell Press
Background: Schizophrenia is a psychiatric disorder typically diagnosed in adulthood and thought to arise from complex interactions between genetic and environmental factors. While inherited genetic variants have long been studied, somatic mutations—those acquired after fertilization—have been less well characterized in psychiatric diseases.
Published in Cell Genomics, this study mined blood-derived genotype arrays from thousands of individuals with and without schizophrenia to search for somatic copy-number variants. By focusing on variants likely to have occurred early in development, the researchers could detect sCNVs present in a mosaic pattern across tissues, including blood, which serves as an accessible proxy for mutations that may also affect the brain.
Somatic mutations differ from inherited (germline) changes because they are present only in a fraction of the body’s cells. The proportion of cells carrying a somatic variant depends on the timing of the mutation: one arising immediately after fertilization may be present in roughly half of the cells, while one occurring later will be found in fewer cells. This principle enables detection of early-developmental sCNVs in blood samples and provides a window into acquired genetic events that could influence brain development and psychiatric outcomes.
NRXN1 recurrent deletions identified in the study remove early exons and may alter local regulatory interactions in a way that affects gene expression. Hi-C chromatin mapping showed allele-specific changes in three-dimensional genome organization around NRXN1 when these 5′ deletions are present, suggesting potential mechanisms by which somatic deletions could disrupt neuronal function.
The second gene, ABCB11, was a surprising discovery. Although primarily recognized for its role in liver biology, further investigation revealed ABCB11 expression in narrow populations of mesocortical and mesolimbic dopaminergic neurons—cells implicated in schizophrenia pathology and targeted by many antipsychotic medications. Recurrent intragenic deletions of ABCB11 were observed in several cases characterized as treatment-resistant, offering a plausible link between somatic disruption and poor drug response.
Moving forward, the research team plans to expand searches for acquired mutations associated with schizophrenia and other neuropsychiatric disorders, including a deeper look at brain-specific somatic events that may not be detectable in blood. The results raise the possibility that somatic deletions or duplications are underexplored contributors to psychiatric disease risk and treatment outcomes.
Funding and disclosures: This work received support from institutional training programs, fellowships, the National Institutes of Health, the Stanley Center for Psychiatric Research, the Brain Somatic Mosaicism Network, the Psychiatric Genomics Consortium, the Allen Discovery Center for Human Brain Evolution, the Howard Hughes Medical Institute, the Suh Kyungbae Foundation, the Chan Zuckerberg Initiative, and other scientific partners. The authors report no conflicts of interest.
About this schizophrenia and genetics research news
Author: Ellie Rose Mattoon
Source: Cell Press
Contact: Ellie Rose Mattoon – Cell Press
Image: Image credited to Neuroscience News
Original Research (open access): “Schizophrenia-associated somatic copy number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions” by Chris Walsh et al., published in Cell Genomics.
Abstract (summary):
Schizophrenia-associated somatic copy number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions
Germline copy-number variants are known contributors to schizophrenia risk, but the role of somatic copy-number variants (sCNVs)—mutations present in only some cells—remains less clear. Using blood-derived genotype arrays from 12,834 schizophrenia cases and 11,648 controls, researchers identified sCNVs while filtering out variants likely arising from clonal blood disorders. Early-developmental sCNVs were enriched in cases compared with controls. Recurrent somatic deletions affecting NRXN1 exons 1–5 were observed in multiple schizophrenia cases, with chromatin conformation data revealing allele-specific loops that may alter regulatory interactions. Recurrent intragenic deletions in ABCB11 were found in several treatment-resistant cases, and ABCB11 expression is enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. These findings point to potential roles for somatic CNVs in schizophrenia risk and encourage further investigation into acquired mutations in psychiatric disorders.