Ancestry-specific and multi-ancestry genome-wide association studies of restless legs syndrome

Abstract Restless legs syndrome is a neurological disorder that disrupts sleep and quality of life, but its genetics have mostly been studied in individuals of European ancestry. Here, we perform GWAS of restless legs syndrome using data from individuals of African, Latin American, and European ancestry, followed by a multi-ancestry meta-analysis. We leverage biobank-based cohorts that established RLS diagnosis using validated clinical criteria, allowing for precise phenotypic characterization. We perform ancestry-specific association studies and post-GWAS analyses to prioritize candidate genes. Our analyses reveal ancestry differences in the genetics of restless legs syndrome. At the MEIS1 and BTBD9 loci, lead variants showed lower allele frequencies and did not reach genome-wide significance in African ancestry. We identify ancestry-specific and shared risk loci, including novel associations near GYPC/TEX51 and PRIMA1 in African ancestry and ISX in Latin American ancestry. The European meta-analysis identifies 11 additional loci and replicates 50 previously reported associations. The combined multi-ancestry analysis finds ten new loci. This multi-ancestry study broadens the genetic understanding of restless legs syndrome, and the absence or reduced frequency of key European restless legs syndrome alleles in individuals of African ancestry provides insights into known epidemiological differences.