African-ancestry-specific variant IKKβ p.Glu502Lys confers high lupus risk

Cutaneous lupus erythematosus (CLE) is an autoimmune disease of the skin, occurring with or without systemic lupus erythematosus (SLE). People with African ancestry have a higher risk than people with other ancestries of developing lupus¹ but have been underrepresented in genetic studies. We whole-genome-sequenced 27,820 Americans with genetically inferred African ancestry from the Diverse Ancestry Cohort, including people with CLE (n = 211) and/or SLE (n = 574). We discovered an association with a rare missense variant in IKBKB, rs115698972G>A, IKKβ^E502K, exclusive to people with African ancestry, conferring an odds ratio (OR) of 5.4 for CLE and 3.3 for SLE. These associations replicated in the All of Us and VA Million Veteran Research Programs for CLE (OR_meta = 3.8, P_meta = 5.3 × 10^-20, n = 1,243) and SLE (OR_meta = 3.2, P_meta = 1.0 × 10^-19, n = 1,697). In this cohort, IKKβ^E502K accounts for 10.4% of CLE cases and 6.4% of SLE cases, confers a high lupus risk, and contributes substantially to the disease prevalence among people with African ancestry. This highlights the value of including diverse ancestries in genetic association studies.