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Schizophrenia Ties to Mosaic CNVs Suggest Early Developmental Origins of the Disease

NEW YORK – New research has unearthed recurrent copy number variants (CNVs) in a subset of cells from individuals with schizophrenia. These mosaic mutation patterns, which included two genes, point to early developmental origins for the disease.

Using array-based genotyping profiles for 12,834 individuals with schizophrenia and more than 11,600 unaffected controls, coupled with a new computational approach, the researchers searched for somatic schizophrenia-associated CNVs, focusing on loci previously linked to clonal blood disorders.

As the team reported in Cell Genomics on Thursday, the analyses pointed to an overrepresentation of somatic CNVs in schizophrenia patients, particularly those suspected to derive from early developmental events. These CNVs — which appeared to originate during embryonic development, leading to alterations in a subset of cells — turned up in 0.91 percent of individuals with schizophrenia, but just 0.51 percent of the unaffected control participants.

The researchers traced recurrent CNVs involving two genes in particular: NRXN1, a gene previously linked to schizophrenia, and a new candidate gene, ABCB11. Five of the cases had recurrent deletions in NRXN1, they reported, while five ABCB11 deletions turned up in schizophrenia patients with resistance to two or more antipsychotic medications.

Together, the results build on prior genetic studies of schizophrenia, the researchers explained, highlighting a role for clonal mosaicism in a subset of individuals with schizophrenia.

"Previous work had suggested that somatic mosaic CNVs could contribute to [schizophrenia], but the evidence was not so clear," senior and corresponding author Christopher Walsh, a researcher affiliated with Boston Children's Hospital and the Broad Institute, said in an email, noting that the new results "firmly establish their role in a modest proportion (0.4 percent or so) of cases."

The findings prompted a series of follow-up analyses, including Hi-C chromatin interaction profiling on neurons derived from human induced pluripotent stem cells, single-molecule in situ hybridization assessments of postmortem brain samples, and analyses of published single-nucleus RNA sequencing data, the team explained.

In the case of NRXN1, for example, the results suggested that recurrent deletions affecting the first five exons of the gene led to new interactions between a noncoding regulatory element and a cryptic promoter, potentially leading to a truncated, dominant-negative form of the gene product.

On the other hand, the recurrent intragenic deletions affecting ABCB11 showed potential ties to treatment resistance in five individuals with schizophrenia, potentially reflecting the gene's enhanced expression in mesocortical and mesolimbic dopaminergic neurons targeted by some antipsychotic drugs.

Given these apparent ties to target neurons and altered treatment response, Walsh suggested that "studies to improve ABCB11 function could lead to drugs with potential therapeutic benefits."