We next explored the virus-specific associations in more detail. Anti-influenza A IgG antibodies were detected in approximately two thirds of study participants (Table 1), and two SNPs mapping to the HLA-DRB1 (MIM: 142857), DQA1 (MIM: 146880), and DQB1 (MIM: 604305) gene regions were identified as independently associated with influenza A seropositivity in the genome-wide SNP screen (Figure 2A). Amino acid position 96 in HLA-DRβ1 was associated more strongly with influenza A serostatus than any SNP or classical HLA allele (omnibus p = 2.6 × 10−16, Table 2) and explained most of the association signals of both independently associated SNPs when included in a conditional analysis. The residual significance of p = 9.5 × 10−4 for rs140012631 and p = 1.0 × 10−4 for rs9269912 might, however, imply that these SNPs tag additional classical or non-classical HLA effects that did not reach our significance threshold. Individuals carrying a glutamine at position 96 were more likely to have detectable levels of anti-influenza A IgG (odds ratio [OR] = 1.68), whereas the presence of a glutamic acid was associated with seronegativity (OR = 0.51, Figure 2B). These two amino acids are carried by the HLA-DRB1∗15:01 and the HLA-DRB1∗01:01 alleles, respectively. They are in almost perfect linkage disequilibrium (LD) with HLA-DQB1∗06:02 and HLA-DQB1∗05:01, respectively (Table S7), which were the most strongly associated classical HLA alleles (Figure 2C). This result is consistent with a recent study associating HLA-DRB1∗15:01 with increased responsiveness to trivalent influenza vaccines in Hispanic children.16 Interestingly, the HLA-DRB1∗15:01-HLA-DQB1∗06:02 haplotype is found in nearly 100% of individuals with narcolepsy (MIM: 161400),17, 18 a condition with strong evidence for an autoimmune basis and with a possible, but still controversial, mechanistic link to influenza infection.19, 20 The same HLA class II haplotype has also been shown to be positively associated with multiple sclerosis (MIM: 126200),21 systemic lupus erythematosus (MIM: 152700),22, 23 and Goodpasture disease (MIM: 233450).24