Genomic loci and molecular genetic mechanisms for hidradenitis suppurativa

Abstract

Background: Hidradenitis suppurativa (HS) is a common, chronic and debilitating inflammatory disease that most commonly affects intertriginous skin. Despite its high heritability, the genetic underpinnings of HS remain poorly understood.

Objectives: To identify genetic signals associated with HS, determine genetic relationships with other diseases and investigate potential molecular genetic mechanisms.

Methods: We performed a genome-wide association meta-analysis of six studies, totalling 4540 patients with HS and > 1 million control participants, and identified genetic correlations with other common diseases. We integrated the HS data with expression quantitative trait loci from 10 trait-relevant tissues, epigenomic and transcriptomic data from human scalp, differential expression data from HS lesions vs. adjacent skin and mesenchymal Hi-C chromatin looping data. To identify functional noncoding variants, we performed transcriptional reporter assays for signals near KLF5 and SOX9.

Results: We identified 11 significant HS signals across 7 loci: 4 corresponded to previously reported associations, 4 represented novel signals within known loci and 3 were signals in newly implicated loci. We identified significant genetic correlations between HS and other inflammatory conditions, particularly inflammatory bowel disease, rheumatoid arthritis, type 2 diabetes mellitus and asthma. We prioritized candidate genes for the 11 signals. The risk allele at KLF5 exhibited 10-fold greater transcriptional activity than the nonrisk allele, while risk alleles at SOX9 showed significantly reduced transcriptional activity.

Conclusions: Our results provide insights into potential genetic mechanisms underlying HS and suggest potential therapeutic targets for this challenging condition.

Graphical Abstract

Figure 1

Hidradenitis suppurativa (HS) genetic association signals. (a) Manhattan plot of the associations between variants and HS in all populations. Variants within 1 Mb of a previously known HS locus are coloured in blue; variants within 1 Mb of a new HS locus (P ≤ 5 × 10^–8) are coloured in red. Loci with asterisks (*) represent multi-signal loci. (b) Variant associations for new HS loci: (left) a signal near SUCNR1 was significantly associated with HS in the all-population analysis; (middle) a signal near NIN was significantly associated with HS in the EUR + AMR stratified analysis; (right) a signal near MXRA7 was significantly associated with HS in men. Chr, chromosome; EUR + AMR, European and admixed American populations.

Figure 2

Hidradenitis suppurativa locus detected in men-only genome-wide association studies (GWAS). (Left) Variants associated with HS in men (top) vs. women (bottom). (Right) Forest plot of men-only and women-only GWAS results. The MXRA7 locus is strong in men and shows consistent direction and strength of effect across all contributing studies. An effect is not detected in any women-only or sex-combined GWAS results. AFR, Black/African population; AoU, All of Us; EUR + AMR, European and admixed American populations; BioVU, BioVU project at Vanderbilt University Medical Center; Chr, chromosome; CI, confidence interval; MGBB, Mass General Brigham Biobank; ProCARE, Program for Research and Care Excellence; UKB, UK Biobank.

Figure 3

Genetic correlation between hidradenitis suppurativa and other complex traits. Green indicates Bonferroni significant correlations. IBD, inflammatory bowel disease; T2D, type 2 diabetes; PCOS, polycystic ovarian syndrome; RA, rheumatoid arthritis.

Figure 4

Differential expression of prioritized candidate genes in lesional vs. nonlesional tissue and in scalp cell types. We prioritized 20 genes that were within 100 kb of a lead variant, or the nearest protein-coding gene if none were within 100 kb, and genes with external evidence of relevance to hidradenitis suppurativa (HS). (Top) Log₂ fold change (FC) of gene expression in HS lesional vs. matched nonlesional tissue. (Bottom) Log₂ FC of gene expression in scalp cell types. Only increased expression in a cell type is shown. To be included, the cell type must be more highly expressed in at least one prioritized gene. Circles show the size of the fold change. Orange = keratinocytes; yellow = melanocytes; green = fibroblasts; purple = immune cells; brown = muscle or endothelial cells. Chr, chromosome

Figure 5

Hidradenitis suppurativa (HS) loci (left) KLF5 and (right) SOX9 may influence expression levels of their target genes in keratinocytes via a regulatory element that appears to be only accessible in keratinocytes. (Top row) Variant associations with HS for the two signals. (Middle left) Genome browser plots showing scalp chromatin accessibility by cell type. The lead variant of KLF5 (rs981625) is located in a keratinocyte-accessible regulatory element that was not seen in other examined cell types (chr13_73465564_73466065) and is strongly conserved across vertebrates. No other linkage disequilibrium (LD) proxies of the lead variant are located in accessible chromatin. KLF5 was more strongly expressed in keratinocytes than in any other cell type [log₂fold change (FC) = 0.56–1.93 for keratinocyte cell clusters, P-values ≤ 4 × 10^–166]. (Bottom left) The rs981625-C allele, which was associated with higher HS risk, showed 10-fold greater transcriptional activity than the rs981625-G reference allele (P = 2.9 × 10^–7). (Middle right) The SOX9 lead variant rs17226067, and its LD proxies rs17825774 and rs17825799 (r² = 1, shown in gold) are located in a region of open chromatin detected in keratinocytes but not in other surveyed cell types (chr17_71519287_71519788); no other LD proxies are located in accessible chromatin. SOX9 was also more highly expressed in hair follicle keratinocyte clusters than other scalp cell types (log₂FC = 0.28–5.19, P-values ≤ 5 × 10^–86). (Bottom right) The three-variant risk haplotype of rs17226067-G, rs17825774-A and rs17825799-A alleles showed more than twofold reduced transcriptional activity vs. the reference AGG haplotype (P = 0.001). cCRE, candidate cis-regulatory element; Chr, chromosome; EV, empty vector.

Figure 6

Both conditionally distinct signals on chromosome 9 exhibit a significant Hi-C chromatin interaction peak in mesenchymal data. (a) Variants associated with hidradenitis suppurativa (HS) at two conditionally distinct signals. (b) Mesenchymal cell Hi-C data anchored around rs1994799, the lead variant for the primary HS signal. (c) Mesenchymal cell Hi-C data anchored around rs1535620, the lead variant for the secondary HS signal. The target regions immediately flanking the anchor regions and target regions with FitHiC Q-values ≥ 0.01 are not shown. Arc colours are scaled by strength of association measured by –log₁₀(P-value), with the darkest lines showing the link with the strongest P-value. Hi-C data in the red box, centred around KLF4, showed significant interactions; no significant interactions were observed around the more proximal gene ACTL7B (grey box). Chr, chromosome.