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<p>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).&#xa0;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.&#xa0;Nine meQTLs were validated, including rs987525 (8q24)–cg16561172 (<i>MYC</i>) (<i>P</i> = 9.6 × 10⁻⁶), which mapped to a mesendoderm-active enhancer upstream of <i>MYC</i>. Genotype × tissue interaction confirmed tissue-specificity (<i>P</i> = 1.00 × 10<sup>− 3</sup>), with stronger effects in oral-derived tissue (saliva). Additional validated SNP-CpG associations involved <i>MAFB</i>–<i>PLCG1</i>, <i>NOG</i>–<i>PPM1E</i>, <i>FOXE1</i>–<i>FRZB</i>, and <i>SPRY2</i>–<i>LGR4</i>. While effect sizes correlated between tissues (<i>r</i> = 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.&#xa0;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.</p>

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Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • 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

摘要

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− 3), 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.