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Identifying the regulatory potential of 7 million SNPs in human neural stem cells

ABSTRACT: Genome-wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNPs) associated with different human phenotypes. Most SNPs are located in non-coding regions of the genome, where a small subset of causal SNPs is thought to contribute to risk by regulating transcription. However, identification of such causal variants remains challenging due to linkage disequilibrium, where blocks of SNPs are inherited together. Here, we performed a massively parallel reporter assay called survey of regulatory elements (SuRE) in human neural stem cells to assess the transcription regulatory potential of 7.1 million SNPs. We identified 7,002 SNPs with regulatory potential (reporter assay quantitative trait loci, raQTLs), thereby increasing the number of putative regulatory variants in neural cell types by one order of magnitude. raQTLs were enriched for enhancers and often coincide with binding sites for transcription factors, such as ZBTB33, YY1, and ETS factors. Overlapping SuRE data with eQTL data pinpointed likely gene-regulatory variants. Overlap with GWAS for seven neuropsychiatric phenotypes identified 187 raQTLs in risk loci containing 183,186 SNPs assessed by SuRE. In conclusion, our SuRE dataset provides a rich source to prioritize genetic variants that may be relevant for disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292348 | GEO | 2026/01/31

REPOSITORIES: GEO

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Project description:Background: The identification of causal variants responsible for disease associations from genome-wide association studies (GWAS) facilitates functional understanding of the disease mechanisms implicated by GWAS. One of the earliest GWAS associations to COPD spans an intragenic region within FAM13A, but the causal variants at this loci have not yet been identified. Massively parallel reporter assays (MPRA) can be used to prioritize functional regulatory variants in a high-throughput manner. Methods: We used an integrated approach using fine-mapping in over 10,000 subjects from COPD GWAS studies, two MPRA experiments, traditional reporter assays, chromatin conformation capture, and CRISPR-based gene editing to characterize COPD-associated regulatory variants in FAM13A in human bronchial epithelial cell lines. Results: Conditional genetic association and fine mapping analyses identified two independent COPD association signals in FAM13A. MPRA identified 45 common functional regulatory variants, and six COPD-associated putative functional variants were prioritized for further functional investigation. Three variants demonstrated significant activity in traditional reporter assays, and one variant, rs2013701, was selected for further testing in the endogenous genomic context based on a direction of effect consistent with postulated mechanisms of FAM13A-mediated COPD susceptibility. CRISPR-based genome editing for this variant confirmed allele-specific effects on FAM13A expression and altered rates of cellular proliferation, providing multiple levels of functional characterization for this COPD-associated variant. Conclusions: Comprehensive screening for regulatory variants near FAM13A identified the presence of extensive functional regulatory variation within a 250kb window of FAM13A in HBECs. Focused functional evaluation of the COPD-associated functional variants in LD with the two independent association signals in this region prioritized the common variant rs2013701, for which multiple parallel lines of functional evidence confirm allelic effects on FAM13A regulation.

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Identifying the regulatory potential of 7 million SNPs in human neural stem cells

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