Schizophrenia (SCZ) is a psychiatric disorder with onset in adulthood, and is thought to be triggered by some combination of environmental factors and genetics. However, the exact cause of the disorder is still not fully understood. Researchers have now identified a correlation between schizophrenia and somatic copy-number variants (sCNVs), a type of mutation that occurs early in development, but after genetic material is inherited. The study, headed by researchers at Boston Children’s Hospital and Harvard Medical School, is one of the first to rigorously describe the relationship between somatic—not inherited—genetic mutations and schizophrenia risk.

“We originally thought of genetics as the study of inheritance. But now we know that genetic mechanisms go way beyond that,” said Chris Walsh, PhD, an investigator at the Howard Hughes Medical Institute and chief of genetics and genomics at Boston Children’s Hospital. “We’re looking at mutations that are not inherited from the parents.” Walsh is senior author of the team’s published paper in Cell Genomics, titled “Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions,” in which the investigators concluded, “Taken together, these data suggest that potential roles of sCNVs in the genetic architecture of SCZ merit further study.”

De novo and rare germline copy-number variants (gCNVs) contribute to up to 5.1–5.5% of schizophrenia (SCZ) cases, with relatively large effect sizes, the team noted. “These gCNVs are usually inherited or represent de novo events thought to arise during gametogenesis.” In contrast with gCNVs, somatic copy-number variants are present in only a fraction of cells in the body, based on when and where a mutation occurred. If a mutation occurs early in development, it is expected that the variant is present throughout the body in a mosaic pattern. “If a mutation occurs after fertilization when there are only two cells, the mutation will be present in half of the cells of the body,” said Walsh. “If it occurs in one of the first four cells, it will be present in about a quarter of the cells of the body, and so on.”

On the basis of this principle, researchers can identify somatic mutations that occurred early in development and are present not only in the brain but also in a fraction of cells in the blood. “Prior studies have shown that non-oncological somatic variants present in more than 1–3% of cells in a tissue are typically shared in all developmental lineages in a mosaic fashion,” the investigators wrote. “The mosaic fraction of variants in blood exhibited a linear relationship with the mosaic fraction in other tissues, suggesting that studying highly mosaic variants in blood might reflect, to an extent, somatic variation in other tissues such as brain.”

For their newly reported study the researchers analyzed genotype-marker data from 12,834 cases and 11,648 controls from the Psychiatric Genomic Consortium (PGC) SCZ cohort. Their analyses identified two genes—NRXN1 and ABCB11—that correlated with schizophrenia cases when disrupted in utero. NRXN1, a gene that helps transmit signals throughout the brain, has been associated with schizophrenia before. However, this is the first study to associate somatic, not inherited, NRXN1 mutations with schizophrenia.

The second gene the researchers identified, ABCB11, is known to encode a liver protein. “That one came out of nowhere for us,” says Eduardo Maury, a student in Harvard-MIT’s MD-PhD program. “There have been some studies associating mutations in this gene with treatment-resistant schizophrenia, but it hasn’t been strongly implicated in schizophrenia per se.”  The authors further wrote “Genes in this transporter family, includingABCB11, have previously been associated with differential response to antipsychotics. However, the exact mechanism by which mutations in these genes might lead to poor response to antipsychotics remains unknown.”

Schizophrenia linked to somatic cell copy number variants
Schizophrenia-associated somatic copy number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions. [Cell Genomics / Maury et al.]

When the team investigated further, they found that ABCB11 is also expressed in specific subsets of dopaminergic (DA) neurons that carry dopamine from the brainstem to the cerebral cortex. Most schizophrenia drugs are thought to act on these cells to decrease an individual’s dopamine levels, so this might explain why the gene is associated with treatment resistance. “Most anti-psychotic medications used to treat SCZ target DA signaling in the brain, but how DA pathways become abnormal in SCZ remains unclear,” they wrote. “Disruption of ABCB11 could alter the function of this key neuronal circuitry in a relatively cell-type-specific manner. While the exact role of ABCB11 on DA neuron physiology or excitatory layer 5 neurons is yet unknown, our results suggest this as an area for further inquiry with potential disease relevance.”

The team is next working towards identifying other acquired mutations that might be associated with schizophrenia. Given that the study analyzed blood samples, it will be important to look at more brain-specific mutations that might have been too subtle or recent in a patient’s life for this analysis to detect. In addition, somatic deletions or duplications might be an under-investigated risk factor associated with other disorders.

“With this study, we show that it is possible to find somatic variants in a psychiatric disorder that develops in adulthood,” said Maury. “This opens up questions about what other disorders might be regulated by these kinds of mutations.”

Noting limitations of their study, the team pointed out. “… studying the functional role of the sCNVs in NRXN1 and ABCB11, and somatic variants in general, will require novel mosaic models such as organoids, or animal models, where specific fractions of cells carry the desired events. Nevertheless, they concluded, “The data presented here represent an initial and preliminary study that is potentially of interest to the field as the role of somatic mutations in general, and sCNV specifically, in disease comes into focus.”

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