Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02

Abstract

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 undertake 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 perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.

Fig. 1

Clinical features of frontal fibrosing alopecia. Scalp with frontal hairline recession (a) involving the temporal areas bilaterally (b), as well as eyebrows (c). Histopathology (d) shows two hair follicles with focal interface changes, and a moderately dense perifollicular lymphoid cell infiltrate with perifollicular fibrosis, characteristic of FFA (×200)

Fig. 2

Manhattan plot showing the P values for the meta-analysis genome-wide association study. Each SNP was tested for association by logistic regression using an additive regression model; the interrupted line indicates the threshold for genome-wide significance (P = 5 × 10⁻⁸); the y axis has been collapsed for better illustration of all genomic signals; the continuous line represents the threshold for suggestive significance (P = 1 × 10⁻⁵); N = 5161 biologically independent subjects (N_cases = 1044 and N_controls = 4145)

Fig. 3

Regional plots of lead signals at loci 15q26.1 and 8q24.22. a Regional plot at locus 15q26.1 (rs34560261); and b Regional plot at locus 8q24.22 (rs760327). The blue lines shows the fine-scale recombination rates (right y axis) estimated from individuals in the 1000 Genomes population; genes are highlighted with horizontal lines; the x axis shows the chromosomal position in Mb; variants within the 95% credible set are highlighted in red

Fig. 4

Regional plot at locus 2p22.2 and CYP1B1 enzyme structure. a Regional plot of lead signal at locus 2p22.2 demonstrating the lead causal variant (rs1800440); the blue lines shows the fine-scale recombination rates (right y axis) estimated from individuals in the 1000 Genomes population; genes are highlighted with horizontal lines; the x axis shows the chromosomal position in Mb; variants within the 95% credible set are highlighted in red (N = 1, posterior probability = 0.98); b CYP1B1 enzyme structure drawn via the SWISS-MODEL repository with the site affected by the residue change from Asparagine (N) to Serine (S) at position 453 magnified (https://swissmodel.expasy.org/repository)