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Massively parallel reporter assays and variant scoring identified functional variants and target genes for melanoma loci and highlighted cell-type specificity

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dc.contributor.author김은영-
dc.date.accessioned2023-03-10T01:35:15Z-
dc.date.available2023-03-10T01:35:15Z-
dc.date.issued2022-12-
dc.identifier.issn0002-9297-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/193247-
dc.description.abstractThe most recent genome-wide association study (GWAS) of cutaneous melanoma identified 54 risk-associated loci, but functional variants and their target genes for most have not been established. Here, we performed massively parallel reporter assays (MPRAs) by using malignant melanoma and normal melanocyte cells and further integrated multi-layer annotation to systematically prioritize functional variants and susceptibility genes from these GWAS loci. Of 1,992 risk-associated variants tested in MPRAs, we identified 285 from 42 loci (78% of the known loci) displaying significant allelic transcriptional activities in either cell type (FDR < 1%). We further characterized MPRA-significant variants by motif prediction, epigenomic annotation, and statistical/functional fine-mapping to create integrative variant scores, which prioritized one to six plausible candidate variants per locus for the 42 loci and nominated a single variant for 43% of these loci. Overlaying the MPRA-significant variants with genome-wide significant expression or methylation quantitative trait loci (eQTLs or meQTLs, respectively) from melanocytes or melanomas identified candidate susceptibility genes for 60% of variants (172 of 285 variants). CRISPRi of top-scoring variants validated their cis-regulatory effect on the eQTL target genes, MAFF (22q13.1) and GPRC5A (12p13.1). Finally, we identified 36 melanoma-specific and 45 melanocyte-specific MPRA-significant variants, a subset of which are linked to cell-type-specific target genes. Analyses of transcription factor availability in MPRA datasets and variant-transcription-factor interaction in eQTL datasets highlighted the roles of transcription factors in cell-type-specific variant functionality. In conclusion, MPRAs along with variant scoring effectively prioritized plausible candidates for most melanoma GWAS loci and highlighted cellular contexts where the susceptibility variants are functional.-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherUniversity of Chicago Press-
dc.relation.isPartOfAMERICAN JOURNAL OF HUMAN GENETICS-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.subject.MESHBiological Assay-
dc.subject.MESHGenome-Wide Association Study-
dc.subject.MESHHumans-
dc.subject.MESHMelanoma* / genetics-
dc.subject.MESHReceptors, G-Protein-Coupled-
dc.subject.MESHSkin Neoplasms* / genetics-
dc.subject.MESHTranscription Factors-
dc.titleMassively parallel reporter assays and variant scoring identified functional variants and target genes for melanoma loci and highlighted cell-type specificity-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Internal Medicine (내과학교실)-
dc.contributor.googleauthorErping Long-
dc.contributor.googleauthorJinhu Yin-
dc.contributor.googleauthorKaren M Funderburk-
dc.contributor.googleauthorMai Xu-
dc.contributor.googleauthorJames Feng-
dc.contributor.googleauthorAlexander Kane-
dc.contributor.googleauthorTongwu Zhang-
dc.contributor.googleauthorTimothy Myers-
dc.contributor.googleauthorAlyxandra Golden-
dc.contributor.googleauthorRohit Thakur-
dc.contributor.googleauthorHyunkyung Kong-
dc.contributor.googleauthorLea Jessop-
dc.contributor.googleauthorEun Young Kim-
dc.contributor.googleauthorKristine Jones-
dc.contributor.googleauthorRaj Chari-
dc.contributor.googleauthorMitchell J Machiela-
dc.contributor.googleauthorKai Yu-
dc.contributor.googleauthorMelanoma Meta-Analysis Consortium-
dc.contributor.googleauthorMark M Iles-
dc.contributor.googleauthorMaria Teresa Landi-
dc.contributor.googleauthorMatthew H Law-
dc.contributor.googleauthorStephen J Chanock-
dc.contributor.googleauthorKevin M Brown-
dc.contributor.googleauthorJiyeon Choi-
dc.identifier.doi10.1016/j.ajhg.2022.11.006-
dc.contributor.localIdA00811-
dc.relation.journalcodeJ00086-
dc.identifier.eissn1537-6605-
dc.identifier.pmid36423637-
dc.identifier.urlhttps://www.sciencedirect.com/science/article/pii/S0002929722004979-
dc.subject.keywordCRISPRi-
dc.subject.keywordGWAS-
dc.subject.keywordGWAS follow-up-
dc.subject.keywordMPRA-
dc.subject.keywordcell of tumor origin-
dc.subject.keywordcell-type specificity-
dc.subject.keywordeQTL-
dc.subject.keywordmelanoma-
dc.subject.keywordtranscription factors-
dc.subject.keywordvariant scoring-
dc.contributor.alternativeNameKim, Eun Young-
dc.contributor.affiliatedAuthor김은영-
dc.citation.volume109-
dc.citation.number12-
dc.citation.startPage2210-
dc.citation.endPage2229-
dc.identifier.bibliographicCitationAMERICAN JOURNAL OF HUMAN GENETICS, Vol.109(12) : 2210-2229, 2022-12-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers

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