Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence, the aetiopathogenesis of FFA remains unknown. We undertook genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and performed statistical meta-analysis. We observed genome-wide significant association with FFA at four loci: 6p21.1, 2p22.2, 8q24.22 and 15q2.1. Within 6p21.1, fine-mapping and conditional analysis indicated that the association is driven by allele HLA-B*07:02 (P=9.44×10−117, OR=5.22). At 2p22.2, Bayesian fine-mapping identified a putative causal missense variant in CYP1B1 (P=2.44x10−11, OR=1.65) encoding the homonymous xenobiotic- and hormone-processing enzyme. At 8q24.22, the most likely causal allele is located within ST3GAL1 (P=2.15x10−8, OR=1.34) which has been studied in the context of T cell homeostasis. At the 15q.26.1 locus, the most likely causal variant is in SEMA4B (P=8.12x10−10, OR=1.52) and co-localises with skin eQTLs (Pcoloc=0.99). A global, untargeted, case-control metabolomic study was performed to pursue the mechanistic relevance of CYP1B1, followed by a case-only gene environment interaction scan which suggested positive interaction between CYP1B1 and exposure to hormonal contraception. Transcriptomic analysis of affected scalp tissue highlighted overrepresentation of transcripts pertinent to IFNγ, IL15 and JAK/STAT signalling. These findings characterise FFA as a genetically predisposed complex immuno-inflammatory disorder driven by HLA-B*07:02 and underpinned by causal variation in genes pertinent to T cell homeostasis and hormone and xenobiotic metabolism.

Genome-wide association study in frontal fibrosing alopecia identifies 4 genomic loci and implicates auto-immunity and xenobiotic exposure in aetiopathogenesis