Fine-mapping genomic loci refines craniofacial malformation risk genes

Craniofacial malformation is a highly heritable birth defect with a multifactorial genomic architecture. Although the largest published genome-wide association study has pinpointed 64 loci associated with abnormal craniofacial morphogenesis, the causal variants and effector genes embedded within these intervals remain unresolved. Here we employed an integrated suite of statistical and functional fine-mapping approaches to these loci and prioritized 17 likely causal single-nucleotide substitutions for craniofacial malformation. We assigned these variants to target genes and interrogated their probable regulatory impact by merging sequence annotations, cranial neural crest-cell chromatin maps, craniofacial tissue quantitative trait loci and rare-variant exome data from affected neonates. Convergent evidence highlighted genes governing epithelial–mesenchymal interactions and osteochondral patterning, including IRF6, FGFR2, SOX9, PAX7, MSX1, TP63, RUNX2, COL2A1, ALX4, EDN1, GRHL3, WNT9B, BMP4, TGFBR2 and TFAP2A, among others, as mediators of pathogenesis. These candidates comprise a tractable set for mechanistic interrogation in organoid and in vivo models aimed at uncovering developmental pathways and therapeutic leverage points. Finally, we show that fine-mapping effect estimates enhance the predictive accuracy of polygenic risk scores for craniofacial malformation across ancestries and present a streamlined high-throughput pipeline for variant refinement.