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Study Finds Mechanism Linking Noncoding Risk Locus, Disease-Related Cellular Phenotypes

NEW YORK — Researchers have described a new mechanistic link between a noncoding disease risk locus identified in a genome-wide association study (GWAS) and disease-related cellular phenotypes.

Genetic risk variants for many neuropsychiatric disorders reside in noncoding regions of the genome and are likely to alter gene expression; however it has been largely unknown which genes they affect and how they do so.

To find out, a team led by Jubao Duan at NorthShore University HealthSystem and the University of Chicago studied the effect of a schizophrenia-associated SNP on two cell line models of neuronal development.

As they described in a study published in Cell Genomics on Tuesday, they used ATAC-sequencing in human induced pluripotent stem cell (hiPSC)-derived neurons and NEUROG2 (NGN2)-induced excitatory neurons (NGN2-Glut) to identify schizophrenia GWAS risk variants that alter chromatin accessibility, also known as allele-specific open chromatin (ASoC) variants.

Next, to conduct functional studies, the researchers edited a particular schizophrenia-related SNP, called rs2027349, at the vacuolar protein sorting 45 (VPS45) locus, which was noted as the most significant ASoC in NGN2-Glu cells.

Their findings showed that this SNP affected the expression not only of two adjacent genes  VPS45 and lncRNA AC244033.2  but also of a distal gene called C1orf54 that was 200 kb away from the SNP. According to the authors, VPS45 has been suggested to play a role in vesicle-mediated protein trafficking and neurotransmitter release, while AC244033.2 and C1orf54 have no known function.

Of note, the transcriptomic changes they found in the neurons were associated with both schizophrenia and other neuropsychiatric disorders, and neurons carrying the risk allele exhibited increased dendritic complexity and hyperactivity.

While the exact molecular mechanisms by which the risk variant functions remain unknown, the authors postulated that a possible cis-coregulation between the three genes it affects may be mediated through promoter/enhancer-promoter chromatin interactions.

Meanwhile, further analysis showed that the genes acted synergistically to confer non-additive effects on disease-relevant cellular phenotypes.

"Long-range gene regulation for neuropsychiatric genetic risk variants has been supported by [a] brain promoter capture Hi-C study," the authors noted. "However, such postulated long-range cis-regulatory effects involving multiple genes and their relevance to cellular phenotypes have not been well established."

Highlighting the study's limitations, the authors mentioned that the observed biological effect of the risk variant did not imply disease causality. "At the individual level, polygenic disease occurs only when perturbations from many genetic risks (or protective) loci and environmental factors break down the systems' robustness or buffering capacity," they wrote.

They added that studying individual disease-risk variants/genes in hiPSC models does not represent a paradigm that can recapitulate the in vivo effects of polygenic risk factors. Rather, it enables researchers to understand disease-risk variants or genes mechanistically.

"Our study reveals that multiple genes at a single GWAS risk locus mediate a compound effect on neural function, providing a mechanistic link between a noncoding risk variant and disease-related cellular phenotypes," the authors concluded.