GWAS and new gene answers

Genomic exploration by Chinese researchers uncovers new information regarding genetic schizophrenia risk

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BEIJING—Schizophrenia is a mental disorder characterized by symptoms such as hallucinations or delusions, movement disorders, reduced emotional expression or pleasure, poor executive functioning, or issues with working memory, according to the National Institute of Mental Health (NIMH), part of the U.S. National Institutes of Health. The condition most often appears between the ages of 16 and 30, though cases in children do occasionally present, and more than 200,000 cases are seen each year in the United States alone.
At present, though there are some answers about the nature of the disease, the pathogenesis of schizophrenia “remains elusive,” according to authors of a recent Nature Communications paper. A team of researchers from the Chinese Academy of Sciences has delved deeper into the genetics of the disease in pursuit of more specific information, and have uncovered related genes and potential targets.
While previous genome-wide association studies (GWAS) have pinpointed more than 180 independent risk loci related to schizophrenia, the authors note in their paper that “how the risk variants in the reported loci confer schizophrenia susceptibility remains largely unknown.” They further explored those risk variants in a paper titled “Functional genomics reveal gene regulatory mechanisms underlying schizophrenia risk.”
The research team used functional genomics—including 30 chromatin immunoprecipitation sequencing (ChIP-Seq) experiments, as reported in the paper—to evaluate the gene regulatory mechanisms related to schizophrenia risk. They found “132 risk single nucleotide polymorphisms (SNPs) that disrupt transcription factor binding” and that “97 of the 132 TF binding-disrupting SNPs are associated with gene expression in human brain tissues.”
The majority of the risk variants that have been identified “are located in non-coding regions, implying that these variants exert their effects through altering gene expression. Consistently, recent studies have shown that schizophrenia-associated variants are significantly enriched in regulatory regions, suggesting that disruption of regulatory function may represent a common mechanism that non-coding genetic variants confer risk of [schizophrenia].”
“Our study revealed new gene regulatory mechanisms affected by schizophrenia risk SNPs, including widespread disruption of POLR2A and CTCF binding … we identified the potential target genes of the [transcription factor] binding–disrupting SNPs through eQTL annotation,” the authors reported. “It is likely that the TF binding–disrupting SNPs confer schizophrenia risk through modulating the expression of these target genes.”
Most promising, the authors note, is that by comparing the target genes they identified with previous work from Gusev et al., they pinpointed 44 overlapping genes, which they say “may represent promising candidates for schizophrenia, as these genes were prioritized by two different methods. In addition, the significant enrichment of nervous system development-related genes among the target genes of the TF binding–disrupting SNPs provides further support for the neurodevelopmental hypothesis of schizophrenia.” CTCF binding was found to be “frequently disrupted by the schizophrenia risk SNPs,” and CTCF has been implicated in previous schizophrenia genetic studies, the authors add, which could represent another target.
This isn’t the only recent news in schizophrenia. The Academy shared news in mid-January announcing that a research group from the Institute of Science and Technology for Brain-Inspired Intelligence, which is affiliated to Fudan University, had found that the volume of putamen (a structure found in the subcortical brain region) in adolescents is indicative of a higher chance of developing schizophrenia after adulthood. Their results came from a computational analysis of more than 10,000 data samples of imaging genetics from more than 20 institutions, as noted in a press release, and the sample “was a longitudinally neuroimaging cohort of about 2,000 healthy adolescents,” per the researchers.
Prior to that, scientists from the Chinese Academy of Sciences and Emory identified several “master keys,” which are risk genes found at the center of a network of genes that play a role in brain function. One such master key is MIR-137. This gene “encodes a microRNA, which regulates hundreds of other genes, many of which are also connected to schizophrenia and autism spectrum disorder,” as noted in a press release. The team created mice that partially lack MIR-137, and found that the mice presented with “learning and memory deficits, repetitive behaviors and impaired sociability,” symptoms of both schizophrenia and autism spectrum disorder.

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