Several SNPs near the hedgehog interacting protein (HHIP) gene were associated with FEV1/FVC at genome-wide significance in CHARGE and SpiroMeta, confirming earlier GWAS findings in FHS10. The hedgehog (Hh)-signaling pathway is crucial in several embryonic development processes, including the branching morphogenesis of the lung20,21. Furthermore, several polymorphisms in three genes of the Hh-signaling pathway (IHH, HHIP, and PTCH1) were significantly associated in a GWAS of adult height22. Several PTCH1 SNPs were also significantly associated with FEV1/FVC in CHARGE, but these associations were not confirmed in SpiroMeta. Epithelial cells produce Hh protein, which binds to its membrane receptor (encoded by PTCH1) on mesenchymal cells and orchestrates tissue and organ patterning. Hh pathway dysfunction during fetal life in humans is responsible for severe lung malformations23,24. In adults, the Hh-signaling pathway may participate in the response of the airway epithelium to injury, such as smoking and hyperoxia25,26.
