Frontal fibrosing alopecia (FFA), a clinical variant of follicular lichen planus, is a highly distressing inflammatory and scarring dermatosis of unknown pathobiology that affects almost exclusively post-menopausal women. Since FFA was first described in 1994, there has been rapid increase in reported incidence, culminating in speculation about likely environmental triggers. There is substantial evidence for an inherited component in the aetiology of FFA, as demonstrated by elevated incidence in first-degree relatives. To test the hypothesis that rare large effect size alleles underlie FFA, whole exome sequencing (WES) was utilised to identify variants shared by affected individuals within each of 12 FFA families of presumed Mendelian inheritance. To investigate the contribution of common genetic variation to disease susceptibility, a two-phase genome-wide association study (GWAS) was performed in a UK and a Spanish cohort in a total of 1,016 cases and 4,145 controls. Scalp skin RNA-seq was undertaken to define the FFA transcriptome. A case-control metabolomic analysis was performed to probe the relevance of xenobiotic processing in disease pathogenesis. Significant association with FFA was observed at genomic loci 2p22.2 (CYP1B1
) and 6p21.1 (HLA-B
), highlighting the role of xenobiotic and hormone metabolism and autoimmunity in the pathogenesis of FFA respectively. Transcriptomic analysis of affected skin implicated both innate and adaptive immune mechanisms. In short, this study provides insight into the genetic basis of FFA by characterising the condition as a complex immuno-inflammatory trait.