Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology

A L Petrin; L A Machado-Paula; H L Keen; L Hovey; B Doolittle; L Dunlay; W Awotoye; X J Xie; E Zeng; A Butali; M L Marazita; J C Murray; L M Moreno-Uribe

doi:10.1007/s00438-026-02474-4

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Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology

Journal article

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Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology

A L Petrin, L A Machado-Paula, H L Keen, L Hovey, B Doolittle, L Dunlay, W Awotoye, X J Xie, E Zeng, A Butali, …

Molecular genetics and genomics : MGG, Vol.301(1), 145

06/23/2026

DOI: 10.1007/s00438-026-02474-4

PMID: 42334621

Appears in UI Libraries Support Open Access

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Abstract

Understanding how genetic variants influence disease risk through molecular mechanisms remains a central challenge in complex disease genetics. Nonsyndromic orofacial clefts (OFCs) exemplify this challenge, with most risk loci residing in non-coding regions. We hypothesized that common genetic variants influence OFC risk by modulating DNA methylation at regulatory elements through methylation quantitative trait loci (meQTLs). We analyzed 10 OFC-associated SNPs against genome-wide DNA methylation profiles in 409 cases and 456 controls, identifying 23 potential meQTLs. Findings were validated using 358 cleft-discordant sibling pairs with MethyLight assays. We performed formal mediation analysis, genotype-tissue interaction and cross-referenced with the mQTL Database to assess developmental timing. Nine meQTLs were validated, including rs987525 (8q24)-cg16561172 (MYC) (P = 9.6 × 10⁻⁶), which mapped to a mesendoderm-active enhancer upstream of MYC. Genotype × tissue interaction confirmed tissue-specificity (P = 1.00 × 10 ), with stronger effects in oral-derived tissue (saliva). Additional validated SNP-CpG associations involved MAFB-PLCG1, NOG-PPM1E, FOXE1-FRZB, and SPRY2-LGR4. While effect sizes correlated between tissues (r = 0.81), formal mediation analysis indicated individual CpG sites do not fully mediate SNP-phenotype relationships, suggesting coordinated epigenetic mechanisms. Most associations showed peak effects during childhood, while 8q24 showed unique adult-specific patterns. We identified genetic variants influencing methylation at craniofacial regulatory elements, and provided a mechanistic link for a major risk locus, 8q24, with tissue-specific effects in saliva. While individual CpG sites did not fully mediate the genetic risk, our findings identified specific regulatory regions where coordinated epigenetic changes may contribute to OFC susceptibility.

Epigenetics

DNA methylation

MeQTLs

Orofacial clefts

Discordant siblings

Cleft lip and palate

UIOWA OA Agreement

Details

Title: Subtitle: Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology
Creators: A L Petrin - University of Iowa
L A Machado-Paula - University of Iowa
H L Keen - University of Iowa
L Hovey - Tufts University
B Doolittle - University of North Carolina at Chapel Hill
L Dunlay - University of Iowa
W Awotoye - University of Iowa
X J Xie - Florida State University
E Zeng - University of Iowa
A Butali - University of Iowa
M L Marazita - University of Pittsburgh
J C Murray - University of Iowa
L M Moreno-Uribe - University of Iowa
Resource Type: Journal article
Publication Details: Molecular genetics and genomics : MGG, Vol.301(1), 145
DOI: 10.1007/s00438-026-02474-4
PMID: 42334621
NLM abbreviation: Mol Genet Genomics
ISSN: 1617-4615
eISSN: 1617-4623
Publisher: Springer Nature
Grant note: R37DE08559 / NIDCR NIH HHS K01DE027995 / NIDCR NIH HHS U01DE020057 / NIDCR NIH HHS
Language: English
Date published: 06/23/2026
Academic Unit: Preventive and Community Dentistry; Oral Pathology, Radiology and Medicine; Biostatistics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Otolaryngology; Iowa Institute of Human Genetics; Orthodontics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Iowa Neuroscience Institute; Dental Research
Record Identifier: 9985176673402771

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