Rosacea is a chronic inflammatory skin disorder with high incidence rate. Although genetic predisposition to rosacea is suggested by existing evidence, the genetic basis remains largely unknown. Here we present the integrated results of whole genome sequencing (WGS) in 3 large rosacea families and whole exome sequencing (WES) in 49 additional validation families. We identify single rare deleterious variants ofLRRC4, SH3PXD2AandSLC26A8in large families, respectively. The relevance ofSH3PXD2A, SLC26A8andLRRfamily genes in rosacea predisposition is underscored by presence of additional variants in independent families. Gene ontology analysis suggests that these genes encode proteins taking part in neural synaptic processes and cell adhesion. In vitro functional analysis shows that mutations inLRRC4, SH3PXD2AandSLC26A8induce the production of vasoactive neuropeptides in human neural cells. In a mouse model recapitulating a recurrentLrrc4mutation from human patients, we find rosacea-like skin inflammation, underpinned by excessive vasoactive intestinal peptide (VIP) release by peripheral neurons. These findings strongly support familial inheritance and neurogenic inflammation in rosacea development and provide mechanistic insight into the etiopathogenesis of the condition.