Cell-type-specific meQTLs extend melanoma GWAS annotation beyond eQTLs and inform melanocyte gene-regulatory mechanisms.
Alleles
Atlases as Topic
Chromatin
/ chemistry
Chromosome Mapping
DNA Methylation
Gene Expression Regulation
Gene Regulatory Networks
Genetic Predisposition to Disease
Genome, Human
Genome-Wide Association Study
Humans
Infant, Newborn
Interferon Regulatory Factors
/ genetics
Male
Melanocytes
/ metabolism
Melanoma
/ genetics
Primary Cell Culture
Quantitative Trait Loci
Skin Neoplasms
/ genetics
Transcriptome
DNA methylation
GWAS
IRF4
MWAS
QTL
colocalization
genome-wide association study
mediation analysis
melanocyte
melanoma
methylome-wide association study
quantitative trait loci
trans-QTL
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
02 09 2021
02 09 2021
Historique:
received:
20
03
2021
accepted:
23
06
2021
pubmed:
23
7
2021
medline:
16
9
2021
entrez:
22
7
2021
Statut:
ppublish
Résumé
Although expression quantitative trait loci (eQTLs) have been powerful in identifying susceptibility genes from genome-wide association study (GWAS) findings, most trait-associated loci are not explained by eQTLs alone. Alternative QTLs, including DNA methylation QTLs (meQTLs), are emerging, but cell-type-specific meQTLs using cells of disease origin have been lacking. Here, we established an meQTL dataset by using primary melanocytes from 106 individuals and identified 1,497,502 significant cis-meQTLs. Multi-QTL colocalization with meQTLs, eQTLs, and mRNA splice-junction QTLs from the same individuals together with imputed methylome-wide and transcriptome-wide association studies identified candidate susceptibility genes at 63% of melanoma GWAS loci. Among the three molecular QTLs, meQTLs were the single largest contributor. To compare melanocyte meQTLs with those from malignant melanomas, we performed meQTL analysis on skin cutaneous melanomas from The Cancer Genome Atlas (n = 444). A substantial proportion of meQTL probes (45.9%) in primary melanocytes is preserved in melanomas, while a smaller fraction of eQTL genes is preserved (12.7%). Integration of melanocyte multi-QTLs and melanoma meQTLs identified candidate susceptibility genes at 72% of melanoma GWAS loci. Beyond GWAS annotation, meQTL-eQTL colocalization in melanocytes suggested that 841 unique genes potentially share a causal variant with a nearby methylation probe in melanocytes. Finally, melanocyte trans-meQTLs identified a hotspot for rs12203592, a cis-eQTL of a transcription factor, IRF4, with 131 candidate target CpGs. Motif enrichment and IRF4 ChIP-seq analysis demonstrated that these target CpGs are enriched in IRF4 binding sites, suggesting an IRF4-mediated regulatory network. Our study highlights the utility of cell-type-specific meQTLs.
Identifiants
pubmed: 34293285
pii: S0002-9297(21)00266-4
doi: 10.1016/j.ajhg.2021.06.018
pmc: PMC8456160
pii:
doi:
Substances chimiques
Chromatin
0
Interferon Regulatory Factors
0
interferon regulatory factor-4
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1631-1646Subventions
Organisme : NCI NIH HHS
ID : R01 CA083115
Pays : United States
Organisme : Cancer Research UK
ID : C588/A19167
Pays : United Kingdom
Informations de copyright
Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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