Integrative genomic analysis of 21 orofacial diseases identifies shared genetic architecture with systemic diseases.

Orofacial diseases are closely linked to systemic health, yet their genetic architecture and causal relationships remain incompletely understood. Here we show that integrative genomic analyses of 21 orofacial diseases in the UK Biobank, combining genome-wide, transcriptome-wide, rare variant association studies and Mendelian randomization, identify 48 novel loci and prioritize 160 putative causal genes. Among these, a synonymous variant in ALDH1A2 associated with periodontitis, encoding a key enzyme in retinoic acid synthesis, reduces translational efficiency, as shown by CRISPR-Cas9 editing. Single-cell RNA sequencing of periodontitis tissues further reveals impaired retinoic acid signaling and a T helper 17-skewed immune phenotype, accompanied by reduced retinoic acid levels in gingival crevicular fluid. Mendelian randomization supports a causal effect of Sjögren's syndrome on lung cancer and stroke, replicated in FinnGen. By contrast, dental caries and periodontitis share substantial genetic architecture with systemic diseases, including enrichment of nicotine-related pathways, without robust evidence of causality. Together, these findings map the genetic landscape of orofacial diseases and clarify their complex links to systemic pathophysiology.