Objectives: To identify genetic determinants of granulomatosis with polyangiitis (Wegener's, GPA). Methods: We carried out a genome-wide association study (GWAS) on 492 GPA cases and 1506 healthy controls (white subjects of European descent), followed by replication of the most strongly associated signals in an independent cohort of 528 cases of GPA and 1228 controls. Results: Genome-wide significant associations were identified in thirty-two single nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA-DPB1 and HLA-DPA1 genes encoding the major histocompatibility complex (MHC) class II, DP beta chain 1, and DP alpha chain 1 proteins, respectively. Peak association signals in these two genes, emanating from the rs9277554 (for DP beta chain 1) and rs9277341 (DP alpha chain 1) SNPs were strongly replicated in an independent cohort (Pcombined = 1.92 x 10(-50) and 2.18 x 10(-39) , respectively). Imputation of classical HLA alleles and conditional analyses revealed the SNP association signal to be fully accounted for by the classical HLA-DPB1*04 allele. An independent single SNP, rs26595, near the SEMA6A (semaphorin 6A) gene on chromosome 5, was also associated with GPA, reaching genome-wide significance in a combined analysis of the GWAS and replication cohort (Pcombined = 2.09 x 10(-8) ). Conclusions: We identified the SEMA6A and HLA-DP loci as significant contributors to risk for GPA, with the HLA-DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of this disease. © 2013 American College of Rheumatology.