| Title: | Genome-wide meta-analysis in lichen sclerosus identifies 14 genomic risk loci |
| Journal: | British Journal of Dermatology |
| Published: | 19 Mar 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41850335/ |
| DOI: | https://doi.org/10.1093/bjd/ljag088 |
Publication 17334
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Abstract
BACKGROUND: Lichen sclerosus (LS) is a common and highly debilitating chronic inflammatory dermatosis that primarily affects genital skin in both females and males. Despite the utility of large genetic studies to reveal pathogenic mechanisms and suggest novel therapeutic targets, the genetic basis of LS remains largely unstudied.</p>
OBJECTIVE: To identify genomic loci at which common genetic variation influences LS susceptibility and establish associated pathogenic mechanisms.</p>
METHODS: Sex-stratified genome-wide association studies of genital LS were performed in three European biobanks (UK Biobank, the Trøndelag Health Study [HUNT] and FinnGen). LS cases were primarily identified via linked electronic health records from primary and/or secondary care. In total 6,681 female cases and 407,255 controls were included, with 970 male cases and 331,484 controls. GWAS were combined through fixed-effect meta-analysis. Further analyses to identify putative causal variants and genes were performed, including statistical fine-mapping, functional annotation and assessment of colocalization with gene expression quantitative trait loci (eQTLs).</p>
RESULTS: The MHC Class II allele HLA-DRB1*12:01 was strongly associated with LS susceptibility in females (OR=2.54, 95%CI=2.28-2.83, P=8.3×10-63) and males (OR=2.30, 95%CI=1.73-3.07, P=1.3×10-8). We found genome-wide significant associations (P<5.0×10-8) at another 12 loci in females, including a potentially causal protein-altering variant in IGFLR1 (rs140952221; OR=0.71, 95% CI=0.67-0.74, P=2.1×10-11). Colocalization with established eQTLs in skin and immune tissues highlighted dysregulated expression of CD247, IL2RB and ALDH2 amongst potential LS pathomechanisms. Evidence was observed for shared genetic effects between the sexes, albeit with diluted effect sizes in males (β=0.42, 95%CI=0.21-0.64, P=9.7×10-5). One further risk locus, at chromosome 5p13.2 was revealed by combined-sex meta-analysis.</p>
CONCLUSIONS: This study provides new insight into the pathogenesis of LS by identifying common genetic variation contributing to disease risk and implicating immune-inflammatory and metabolic pathways as potential future drug targets.</p>
18 Authors
- Nick Dand
- Tuntas Rayinda
- Eeva Silz
- Laurent F Thomas
- Jake R Saklatvala
- Sheila M McSweeney
- Chuin Ying Ung
- Evangelos Christou
- Fiona Lewis
- Johannes Kettunen
- Laura Huilaja
- Ben M Brumpton
- Kristian Hveem
- Mari Løset
- Kaisa Tasanen
- John A McGrath
- Michael A Simpson
- Christos Tziotzios
1 Application
| Application ID | Title |
|---|---|
| 15147 | Genetic epidemiology of psoriasis and other inflammatory skin diseases |
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