High-resolution African HLA resource uncovers HLA-DRB1 expression effects underlying vaccine response: script for testing amino-acid correlation

How human genetic variation contributes to vaccine immunogenicity and effectiveness is unclear, particularly in infants from Africa. We undertook genome-wide association analyses of eight vaccine antibody responses in 2,499 infants from three African countries and identified significant associations across the human leukocyte antigen (HLA) locus for five antigens spanning pertussis, diphtheria and hepatitis B vaccines. Using high-resolution HLA typing in 1,706 individuals from 11 African populations we constructed a continental imputation resource to fine-map signals of association across the class II HLA observing genetic variation explaining up to 10% of the observed variance in antibody responses. Using follicular helper T-cell assays, in silico binding, and immune cell eQTL datasets we find evidence of HLA-DRB1 expression correlating with serological response and inferred protection from pertussis following vaccination. This work improves our understanding of molecular mechanisms underlying HLA associations that should support vaccine design and development across Africa with wider global relevance. This release contains a bespoke script for comparing effect estimates and P-values derived for pertussis vaccine response measures from the VaccGene cohort, and those for self-reported whooping cough in the ALSPAC cohort described in the following publication: McMahon G, Ring SM, Davey-Smith G, Timpson NJ. Genome-wide association study identifies SNPs in the MHC class II loci that are associated with self-reported history of whooping cough. Hum Mol Genet. 2015 Oct 15;24(20):5930-9. doi: 10.1093/hmg/ddv293. Epub 2015 Jul 30. PMID: 26231221; PMCID: PMC4581602. There is an R script alongside the summmary statistics from the ALSPAC analysis (WC_aa_associations.txt), statistics for the three pertussis antibody responses: toxin (filtered_aa_stats_1.txt), FHA (filtered_aa_stats_2.txt), and pertactin (filtered_aa_stats_3.txt). A list of variants independent of tight linkage disequilibrium (r2<0.35) is also provided (Burkina_Johannesburg_Uganda_amino_0.35.prune.in).