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Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA association for a human disease. We have conducted a genome-wide association study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC association through high-resolution imputation at classicalHLA loci, identified HLA-A*29:02 as the principalMHCassociation (odds ratio (OR) 5 157.5, 95% CI 91.6-272.6, P = 6.6 × 10-74). We also identified two novel susceptibility loci at 5q15 nearERAP2 (rs7705093;OR 5 2.3,95%CI 1.7-3.1, for the T allele,P = 8.6 × 10-8) and at 14q32.31 in theTECPR2 gene (rs150571175;OR 5 6.1,95%CI 3.2-11.7, for theAallele,P = 3.2 × 10-8). The association nearERAP2was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 × 10-9). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly associated with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic re

Copy-number variation (CNV) is a major contributor to human genetic variation. Recently, CNV associations with human disease have been reported. Many genome-wide association (GWA) studies in complex diseases have been performed with sets of biallelic single-nucleotide polymorphisms (SNPs), but the available CNV methods are still limited. We present a new method (TriTyper) that can infer genotypes in case-control data sets for deletion CNVs, or SNPs with an extra, untyped allele at a high-resolution single SNP level. By accounting for linkage disequilibrium (LD), as well as intensity data, calling accuracy is improved. Analysis of 3102 unrelated individuals with European descent, genotyped with Illumina Infinium BeadChips, resulted in the identification of 1880 SNPs with a common untyped allele, and these SNPs are in strong LD with neighboring biallelic SNPs. Simulations indicate our method has superior power to detect associations compared to biallelic SNPs that are in LD with these SNPs, yet without increasing type I errors, as shown in a GWA analysis in celiac disease. Genotypes for 1204 triallelic SNPs could be fully imputed, with only biallelic-genotype calls, permitting association analysis of these SNPs in many published data sets. We estimate that 682 of the 1655 unique loci reflect deletions; this is on average 99 deletions per individual, four times greater than those detected by other methods. Whereas the identified loci are strongly enriched for known deletions, 61% have not been reported before. Genes overlapping with these loci more often have paralogs (p = 0.006) and biologically interact with fewer genes than expected (p = 0.004).