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Perturbation of the insomnia WDR90genome-wide association studies locus pinpoints rs3752495 as a causal variant influencing distal expression of neighboring gene, PIG-Q
| العنوان: | Perturbation of the insomnia WDR90genome-wide association studies locus pinpoints rs3752495 as a causal variant influencing distal expression of neighboring gene, PIG-Q |
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| المؤلفون: | Sonti, Shilpa, Littleton, Sheridan H, Pahl, Matthew C, Zimmerman, Amber J, Chesi, Alessandra, Palermo, Justin, Lasconi, Chiara, Brown, Elizabeth B, Pippin, James A, Wells, Andrew D, Doldur-Balli, Fusun, Pack, Allan I, Gehrman, Phillip R, Keene, Alex C, Grant, Struan F A |
| المصدر: | Sleep; July 2024, Vol. 47 Issue: 7 |
| مستخلص: | Although genome-wide association studies (GWAS) have identified loci for sleep-related traits, they do not directly uncover the underlying causal variants and corresponding effector genes. The majority of such variants reside in non-coding regions and are therefore presumed to impact cis-regulatory elements. Our previously reported ‘variant-to-gene mapping’ effort in human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs), combined with validation in both Drosophilaand zebrafish, implicated phosphatidyl inositol glycan (PIG)-Qas a functionally relevant gene at the insomnia “WDR90” GWAS locus. However, importantly that effort did not characterize the corresponding underlying causal variant. Specifically, our previous 3D genomic datasets nominated a shortlist of three neighboring single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium within an intronic enhancer region of WDR90that contacted the open PIG-Qpromoter. We sought to investigate the influence of these SNPs collectively and then individually on PIG-Qmodulation to pinpoint the causal “regulatory” variant. Starting with gross level perturbation, deletion of the entire region in NPCs via CRISPR-Cas9 editing and subsequent RNA sequencing revealed expression changes in specific PIG-Qtranscripts. Results from individual luciferase reporter assays for each SNP in iPSCs revealed that the region with the rs3752495 risk allele (RA) induced a ~2.5-fold increase in luciferase expression. Importantly, rs3752495 also exhibited an allele-specific effect, with the RA increasing the luciferase expression by ~2-fold versus the non-RA. In conclusion, our variant-to-function approach and in vitro validation implicate rs3752495 as a causal insomnia variant embedded within WDR90while modulating the expression of the distally located PIG-Q.Graphical Abstract |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 01618105 15509109 |
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| DOI: | 10.1093/sleep/zsae085 |