Genome-wide meta-analysis implicates mediators of hair follicle development and morphogenesis in risk for severe acne

Abstract

Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin for which five genetic risk loci have so far been identified. Here, we perform a genome-wide association study of 3823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identify 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease. Likely causal variants disrupt the coding region of WNT10A and a P63 transcription factor binding site in SEMA4B. Risk alleles at the 1q25 locus are associated with increased expression of LAMC2, in which biallelic loss-of-function mutations cause the blistering skin disease epidermolysis bullosa. These findings indicate that variation affecting the structure and maintenance of the skin, in particular the pilosebaceous unit, is a critical aspect of the genetic predisposition to severe acne.

Fig. 1

Acne association at the 2q35 locus (WNT10A). a Regional acne association plot, variants coloured according to the degree of LD (r²) with the lead SNP (rs121908120, WNT10A:p.F228I). b Location of the rs121908120, p.F228I with respect to the WNT10A gene structure. c Partial three dimensional predicted protein structure incorporating phenylalanine (risk, left) or isoleucine (protective, right) at position 228 (SWISS-MODEL repository). d Forest plot indicating the difference in the effect size of the acne association between males and females for rs121908120. Error bars represent 95% confidence intervals for estimated odds ratios

Fig. 2

Acne association signal at the 15q26.1 locus (SEMA4B). a ChIP-Seq read signal intensities of TP63 binding on two samples from human neonatal foreskin keratinocytes. b Sequence logo of the TP63-binding motif highlighting the risk and protective alleles for rs34560261. The invariant cytosine (position 14) is substituted by a thymine. c Regional acne association plot, variants are coloured according to the degree of LD (r²) with the lead SNP (rs34560261). d SEMA4B not sun exposed skin eQTL from GTEx. e SEMA4B sun exposed skin eQTL from GTEx. f SEMA4B skin eQTL from MuTHER study; * rs1399238 in LD with rs34560261 (r² = 0.66) (rs34560261 was not present in the MuTHER dataset)