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Perturbation of the insomnia WDR90 genome-wide association studies locus pinpoints rs3752495 as a causal variant influencing distal expression of neighboring gene, PIG-Q

生物 全基因组关联研究 遗传学 增强子 单核苷酸多态性 基因座(遗传学) 连锁不平衡 等位基因 诱导多能干细胞 基因 基因表达 基因型 胚胎干细胞
作者
Shilpa Sonti,Sheridan H. Littleton,Matthew C. Pahl,Amber Zimmerman,Alessandra Chesi,Justin Palermo,Chiara Lasconi,Elizabeth Brown,James A. Pippin,Andrew D. Wells,Fusun Doldur-Balli,Allan I Pack,Phillip R. Gehrman,Alex C. Keene,Struan F.A. Grant
出处
期刊:Sleep [Oxford University Press]
卷期号:47 (7) 被引量:1
标识
DOI:10.1093/sleep/zsae085
摘要

Abstract 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 Drosophila and zebrafish, implicated phosphatidyl inositol glycan (PIG)-Q as 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 WDR90 that contacted the open PIG-Q promoter. We sought to investigate the influence of these SNPs collectively and then individually on PIG-Q modulation 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-Q transcripts. 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 WDR90 while modulating the expression of the distally located PIG-Q.

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