rs1044516 (IRF6): Cleft Lip and Palate Risk Variant

Key takeaways

• rs1044516 is in the 1q32 chromosomal region near IRF6, a gene consistently linked to non-syndromic cleft lip with or without cleft palate (CL/P), one of the most common birth defects worldwide.
• The association at this locus was confirmed across European, Asian, African, and Central and South American ancestry groups in a GWAS of 6,480 participants.
• GTEx data show the ALT allele is associated with reduced IRF6 expression in multiple tissues, including tibial nerve, testis, spleen, esophagus, and subcutaneous fat.
• This is a replicated locus; prior GWASs had already identified it as a CL/P risk region before the multi-ethnic study confirmed it.

What the research says The 1q32 locus near IRF6 has been identified in multiple GWASs as a risk site for non-syndromic CL/P, which affects approximately 1 in 700 newborns and arises from a combination of genetic and environmental factors. A multi-ethnic GWAS of 6,480 participants (823 unrelated cases, 1,700 unrelated controls, and 1,319 case-parent trios) spanning European, Asian, African, and Central and South American ancestry groups confirmed genome-wide significant association at this locus alongside other established CL/P genes including PAX7, ARHGAP29, and NTN1. The study authors noted that all known CL/P risk loci collectively do not account for all genetic variance in the condition.

Reported associations

• Non-syndromic cleft lip with or without cleft palate: This locus reached genome-wide significance in a multi-ethnic GWAS of 6,480 participants (823 cases, 1,700 controls, 1,319 case-parent trios) across four ancestry groups, replicating associations reported in earlier GWASs. No variant-specific odds ratio is provided in the available study text.

Evidence quality The association at this locus is a replication finding, not a novel discovery in the provided study. The multi-ethnic design (n=6,480, spanning European, Asian, African, and Central and South American ancestry groups) provides cross-population support. The study lists this locus alongside other well-established CL/P loci without providing variant-specific p-values or effect sizes in the available summary, limiting quantitative interpretation for rs1044516 individually. The prior GWAS replications noted by the study authors add confidence in the overall locus, though the variant-level data available here are descriptive rather than quantitative.

Tissue-specific expression effects

• IRF6: The ALT allele is linked to reduced expression in tibial nerve, testis, spleen, the gastroesophageal junction of the esophagus, the muscular layer of the esophagus, and subcutaneous fat tissue GTEx Portal
• ENSG00000301103 (a nearby gene): Reduced expression in testis tissue GTEx Portal
• TRAF3IP3: Increased expression in whole blood GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.