Hidradenitis suppurativa GWAS identifies 12 loci that implicate misdirected keratinocyte migration in pathogenesis

Summary: Abstract Body: Hidradenitis suppurativa (HS) is a prevalent inflammatory skin disease. The HS Genetics Consortium facilitates global collaborations for conducting and translating HS GWAS. We report a large diverse HS GWAS meta-analysis with 6,500 HS cases. We identify 12 risk loci, including six new loci and new risk haplotypes at two previously reported loci. In silico functional genomic methods identify a core gene module of 55 genes across 9 loci that share genetic mechanisms, suggesting coordinated regulation in HS pathogenesis. We map these genes to a population of keratinocytes in HS skin that has EMT features and localizes to subsets of epithelial tendrils and tunnels, suggesting that the GWAS gene module is contributing to misdirected keratinocyte migration in HS pathogenesis. Genetic correlation (GC) analyses and PheWAS conducted with individual variants and a multi-ancestry HS polygenic risk score identify new disease comorbidities that have clinical implications for patients, including infection susceptibility. We discover a strong negative GC between HS and IBD, providing an opportunity to improve drug safety. Atlas Khan³, Errol Prens⁴, Alice Braun^{5, 15}, Lee Wheless⁶, Lam C. Tsoi⁷, Theodore Drivas⁸, Marylyn Ritchie⁹, Amir Hossein Saeidian¹⁰, Hákon Hákonarson¹⁰, Nick Dand¹¹, Jonathan Barker¹¹, Michael Simpson¹¹, Jake Saklatvala¹¹, Brian Kirby¹², Maris Teder-Laving¹³, Külli Kingo¹³, M Geoffrey Hayes¹⁴, John Connolly¹⁰, Frank Mentch¹⁰, Patrick Sleiman¹⁰, Olivia D. Perez¹, George Hripcsak³, Chunhua Wang³, Stephan Ripke¹⁵, Krzysztof Kiryluk³, Johann E. Gudjonsson⁷, Kelsey Van Straalen⁷, Lynn Petukhova^{1, 2} 1. Dermatology, NYU Langone Health, New York, NY, United States. 2. Population Health, NYU Langone Health, New York, NY, United States. 3. Columbia University, New York, NY, United States. 4. Erasmus Universiteit Rotterdam, Rotterdam, ZH, Netherlands. 5. Charite - Universitatsmedizin Berlin, Berlin, BE, Germany. 6. Vanderbilt University Medical Center, Nashville, TN, United States. 7. University of Michigan, Ann Arbor, MI, United States. 8. University of Pennsylvania, Philadelphia, PA, United States. 9. University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States. 10. The Children's Hospital of Philadelphia, Philadelphia, PA, United States. 11. King's College London, London, England, United Kingdom. 12. University College Dublin, Dublin, Leinster, Ireland. 13. Tartu Ulikool, Tartu, Tartu County, Estonia. 14. Northwestern University Feinberg School of Medicine, Chicago, IL, United States. 15. Broad Institute, Cambridge, MA, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics