Age-related macular degeneration (AMD) risk variants in the complement system point to the important role of immune response and inflammation in the pathogenesis of AMD. Although the human leukocyte antigen (HLA) region has a central role in regulating immune response, previous studies of genetic variation in HLA genes and AMD have been limited by sample size or incomplete coverage of the HLA region by first-generation genotyping arrays and imputation panels. Here, we conducted a large-scale HLA fine-mapping study with 4841 AMD cases and 23 790 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohort. Genotyping was conducted using custom Affymetrix Axiom arrays, with dense coverage of the HLA region. Classic HLA polymorphisms were imputed using SNP2HLA, which utilizes a large reference panel to provide improved imputation accuracy of variants in this region. We examined a total of 6937 SNPs and 172 classical HLA alleles, conditioning on established AMD risk variants, which revealed novel associations with two non-synonymous SNPs in perfect linkage disequilibrium, rs9274390 and rs41563814 (odds ratio (OR) = 1.21; P = 1.4 × 10 − 11 ) corresponding to amino-acid changes at position 66 and 67 in HLA-DQB1, respectively, and the DQB1*02 classical HLA allele (OR = 1.22; P = 3.9 × 10 − 10 ) with the risk of AMD. We confirmed these association signals, again conditioning on established risk variants, in the MMAP data set of subjects with advanced AMD (rs9274390/rs41563814: OR = 1.28; P = 1.30 × 10 − 3 , DQB1*02: OR = 1.32; P = 9.00 × 10 − 4 ). These findings support a role of HLA class II alleles in the risk of AMD. European Journal of Human Genetics (2016) 24, 1049-1055; doi:10.1038/ejhg.2015.247; published online 6 January 2016 INTRODUCTION Age-related macular degeneration (AMD) is a complex, late-onset vision disorder, which is the leading cause of blindness among the elderly in developed countries. [1][2][3][4] Immune response and inflammation play a causal role in the pathogenesis and progression of AMD. [5][6][7][8][9][10][11] The human leukocyte antigen (HLA) region on chromosome 6p21.31 encodes gene products that regulate immune response. Drusen, a pathologic hallmark of AMD, contain HLA class II antigens, 12 and increased HLA class II immunoreactivity has been associated with drusen formation, 13 suggesting that HLA may influence the development of AMD. Although a few small candidate gene studies found that certain HLA class I and class II polymorphisms were associated with a predisposition to AMD, 14,15 the largest genome-wide association study (GWAS) meta-analysis conducted by the AMD Gene Consortium, which included more than 77 000 subjects, did not identify any HLA polymorphisms that were independently associated with the risk of AMD. 16 The AMD Consortium meta-analysis, although well powered to detect common variants of small effect, included a number of studies that utilized genotyping arrays, with array density ranging from 165 770 ...