Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes

Abstract

Rosacea is a common, chronic skin disease of variable severity with limited treatment options. The cause of rosacea is unknown, but it is believed to be due to a combination of hereditary and environmental factors. Little is known about the genetics of the disease. We performed a genome-wide association study (GWAS) of rosacea symptom severity with data from 73 265 research participants of European ancestry from the 23andMe customer base. Seven loci had variants associated with rosacea at the genome-wide significance level (P < 5 × 10-8). Further analyses highlighted likely gene regions or effector genes including IRF4 (P = 1.5 × 10-17), a human leukocyte antigen (HLA) region flanked by PSMB9 and HLA-DMB (P = 2.2 × 10-15), HERC2-OCA2 (P = 4.2 × 10-12), SLC45A2 (P = 1.7 × 10-10), IL13 (P = 2.8 × 10-9), a region flanked by NRXN3 and DIO2 (P = 4.1 × 10-9), and a region flanked by OVOL1and SNX32 (P = 1.2 × 10-8). All associations with rosacea were novel except for the HLA locus. Two of these loci (HERC-OCA2 and SLC45A2) and another precedented variant (rs1805007 in melanocortin 1 receptor) with an association P value just below the significance threshold (P = 1.3 × 10-7) have been previously associated with skin phenotypes and pigmentation, two of these loci are linked to immuno-inflammation phenotypes (IL13 and PSMB9-HLA-DMA) and one has been associated with both categories (IRF4). Genes within three loci (PSMB9-HLA-DMA, HERC-OCA2 and NRX3-DIO2) were differentially expressed in a previously published clinical rosacea transcriptomics study that compared lesional to non-lesional samples. The identified loci provide specificity of inflammatory mechanisms in rosacea, and identify potential pathways for therapeutic intervention.

Figure 1.

Manhattan plot of single-nucleotide polymorphisms in the rosacea GWAS group. The Manhattan plot depicts the distribution of association test results versus genomic position, with chromosomes 1 to 22, and X arranged along the X axis. The Y axis represents –log10 (P values). The P value threshold for declaring statistical significance at the GWAS level, P = 5 × 10⁻⁸, is indicated by the gray line. Loci with P < 5 × 10⁻⁸ are labeled with the name of the nearest gene. The MC1R gene association is annotated on the plot as well.

Figure 2.

Reanalysis of previously published mRNA expression in three rosacea subtypes (7). Samples from patients with PPR, ETR and PhR were compared with samples from healthy volunteers. The heatmap and hierarchical clustering of fold changes comparing rosacea samples against healthy signatures for each subtype shows that the three subtypes were highly similar with erythematotelangiectatic and PhR appearing more closely related than PPR (A). Differential expression analysis of selected genes showed that five genes in the eight gene regions that were associated with rosacea were differentially regulated in rosacea gene expression data (PSMB9_HLA-DMA, HERC2 and DIO2_NRX3) (B).