Schizophrenia associated with non-genetic mutations

summary: Researchers have found a link between schizophrenia and somatic copy number variations, mutations that occur after inheritance.

In this study, genotypic marker data from more than 20,000 blood samples were scrutinized to identify two genes, NRXN1 and ABCB11, that, when disrupted during development, correlated with schizophrenia. NRXN1 is known to help transmit signals throughout the brain, and has been linked to schizophrenia, but non-inherited mutations were suggested to be involved. is the first time.

ABCB11, a gene previously associated with treatment-resistant schizophrenia, also showed a correlation, revealing a new understanding of the genetic mechanisms involved in schizophrenia.

Important facts:

1. This study identifies a correlation between schizophrenia and somatic copy number mutations, mutations that are not inherited from a parent.
2. Two genes, NRXN1 and ABCB11, were found to be associated with schizophrenia when disrupted during intrauterine development.
3. The discovery of an association between ABCB11 and schizophrenia was unexpected and provided new insight into the genetic complexity of this disorder.

sauce: Celpress

Schizophrenia, an adult-onset psychiatric disorder, is thought to be caused by a combination of environmental factors and genetics, but the exact cause is still not fully understood.

In a study published in a journal cell genomics On July 6, researchers discovered a correlation between schizophrenia and somatic copy number variations. Somatic copy number variation is a type of mutation that occurs after inheritance of genetic material early in development.

This study is one of the first to rigorously describe the relationship between non-inherited somatic genetic mutations and schizophrenia risk.

“We originally thought of genetics as the study of heredity. Yes, says lead author Chris Walsh, director of genetics and genomics at Boston Children’s Hospital.

“We are looking at mutations that are not inherited from parents.”

Researchers analyzed data for genotypic markers from more than 20,000 blood samples from people with and without schizophrenia, collected from the Psychiatric Genomics Consortium.

They finally identified two genes.NRXN1 and ABCB11— it correlated with cases of schizophrenia when interrupted in the womb. NRXN1genes that help transmit signals throughout the brain have been previously associated with schizophrenia.

However, this is the first study to link somatic cells rather than genetics. NRXN1 Mutation due to schizophrenia.

Unlike hereditary mutations that are present in all cells of the body, somatic mutations are present only in some cells, based on when and where the mutation occurred. If mutations occur early in development, they are expected to be present in a mosaic pattern throughout the body.

Based on this principle, researchers can identify somatic mutations that occur early in development and are present not only in the brain but also in some cells in the blood.

“If a mutation occurs when there are only two cells after fertilization, the mutation will be present in half the cells of the body,” Walsh said.

“If it occurs in one of the first four cells, it is present in about a quarter of the cells in the body, and so on.”

The second gene the researchers identified was ABCB11, It is best known to encode liver proteins.

“It just popped out of nowhere for us,” says Eduardo Morley, a student in the MD-PhD program at Harvard MIT.

“Although some studies have linked mutations in this gene to treatment-resistant schizophrenia, it is not strongly associated with schizophrenia per se.”

After further investigation by the team, we found that: ABCB11 It is also expressed in a very specialized subset of neurons that carry dopamine from the brainstem to the cerebral cortex.

Most schizophrenia drugs are thought to act on these cells to lower dopamine levels in individuals, which may explain why this gene is associated with treatment resistance.

Next, the team is working to identify other acquired mutations that may be associated with schizophrenia. Given that this study analyzed blood samples, it is important to focus on more brain-specific mutations that were either too subtle to be detected by this analysis or may have occurred recently in the patient’s life. would be In addition, somatic deletions or duplications may be understudied risk factors associated with other diseases.

“This study shows that it is possible to find somatic mutations in adult-onset psychiatric disorders,” Morley said.

“This raises the question of what other disorders are controlled by this kind of mutation.”

Funding: This research was supported by the Harvard/MIT MD-PhD Program, Biomedical Informatics and Data Science Training Program, Ruth L. Kirshstein NRSA F31 Fellowship, National Institutes of Health, Stanley Psychiatric Research Center, Brain-Body Mosaicism Network it was done. , Psychiatry Genomics Consortium, Allen Discovery Center for Human Brain Evolution, Howard Hughes Medical Institute, Seo Kyungbae Foundation, Chan Zuckerberg Initiative and Science Interface. The authors declare no conflict of interest.

About this schizophrenia and genetics research news

author: Ellie Rose Mattoon
sauce: Celpress
contact: Ellie Rose Mattoon – Cell Press
image: Image credited to Neuroscience News

Original research: open access.
“12,834 schizophrenia-associated somatic cell copy number mutations revealed recurrent NRXN1 and ABCB11 disruptionsBy Chris Walsh et al. cell genomics

overview

12,834 schizophrenia-associated somatic cell copy number mutations revealed recurrent NRXN1 and ABCB11 disruptions

Germline copy number variants (CNVs) contribute to the risk of schizophrenia (SCZ), but the contribution of somatic CNVs (sCNVs) present in some but not all cells remains unclear.

We used blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls to filter sCNVs at loci recurrently mutated in clonal hematologic disease to identify sCNVs. .

sCNVs, presumably early in development, were more common in cases (0.91%) than in controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5. NRXN1 Genes in 5 SCZ cases. Hi-C map reveals formation of ectopic allele-specific loops between latent cryptic promoters and non-coding Sith-5′ deletion regulatory element NRXN1.

We also observed recurrent intragenic deletions. ABCB11encoded a transporter involved in antipsychotic responses in five treatment-resistant SCZ cases, and showed that: ABCB11 is particularly rich in neurons that form dopaminergic projections in the mesocortex and mesolimbic system.

Our results indicate a potential role of sCNVs in SCZ risk.