The Genomics of Oral Poliovirus Vaccine Response in Bangladeshi Infants

The success of Oral Poliovirus Vaccine (OPV) in eradicating poliovirus has set an example for the immense potential of oral vaccines in preventing enteric infections. It is widely considered the standard for oral vaccines aiming to elicit a mucosal immune response. Despite being validated in diverse populations worldwide, there still remain some individuals that fail to mount an adequate response to vaccination with OPV. It has been hypothesized that this may be due to host genetics, as the heritability is estimated to be high (60%) and there have been ethnic differences in response. To address this question we conducted a genome-wide association study (GWAS) in 357 Bangladeshi children comparing individuals that fail to mount an immune response to high responders of OPV. Four different approaches were conducted to elucidate genetic risk loci: (1) a traditional GWAS analysis, (2) a correlation of the GWAS results with signatures of positive selection, (3) an application of gene-level methods to the GWAS results, and (4) an application of pathway-level methods to the GWAS results. Because there is no consensus as to the best gene- and pathway-level methods, a simulation experiment was conducted to systematically evaluate their relative performance. The traditional GWAS assessed the association of 6.6 million single nucleotide polymorphisms (SNPs) across the human genome, adjusted for stunting (height-for-age Z-score (HAZ) < -2). While there were not any genome-wide significant results (P<5x10-8), several suggestive associations were found on chromosomes 7 and 14 (P<5x10-6). On chromosome 7, the top association was found at rs55906254 (OR=0.31, P=3.5x10-6). Found upstream of SHH (sonic hedgehog), the minor allele of this SNP conferred decreased odds of high seropositive status versus seronegative. On chromosome 14, the top association was downstream of MAPK1IP1L (mitogen-activated protein kinase 1 interacting protein 1-like) at rs113427985 (OR=0.22, P=2.9x10-6). To measure regions under positive selection, the cross-population extended haplotype homozygosity (XP-EHH) was calculated. To correlate these with the GWAS results, a filter was used in which SNPs had to have a P-value from the GWAS less than 0.001 and a P-value from the selection scan below 0.01. A total of 32 SNPs reached this threshold, half of which were between FAM86A (family with sequence similarity 86, member A) and RBFOX1 (RNA-binding protein, fox-1 homolog). The non-ancestral alleles of these SNPs were associated with high seropositive status. Therefore, it is likely that mutations arose in this region that were beneficial to either OPV immunity or another ancestral pathogen and were preserved. Before the gene- and pathway-level methods were applied to the OPV GWAS, a simulation experiment was conducted to determine which methods were the best. These methods were developed to aggregate signals from the GWAS into gene- and pathway-level units, increasing the power to detect associations and offering biological interpretation. Using genotypic data from the Wellcome Trust Case Control Consortium (WTCCC), a phenotype was simulated assuming an additive polygenic model. A total of 12 gene-level methods and 10 pathway-level methods were systematically evaluated. The gene-level method with the best balance of sensitivity and specificity was VEGAS using only the top 10% of the associated SNPs within the gene. MAGENTA and GSA-SNP had the best performance of all the pathway-level methods. These methods were then applied to the GWAS of OPV. The gene-level results highlighted the potential role of histone modifications as the top results included many histone marks within histone cluster 1 on chromosome 6. Pathway-level methods using the Gene Ontology Biological Processes showed enrichment in gene sets related to cyclic AMP as a second messenger and its relationship with G-protein signaling. Additional associations were found in neurological development. Taken together, this dissertation seeks to elucidate the host genomics of immunity to OPV. The four different approaches were complementary to each other, highlighting different genes and pathways that may relate to the underlying mechanisms of the immunological response. The population-level results may be related to the individual response. Further investigation into the associations may reveal potential adjuvants and improved vaccines, not only for oral poliovirus vaccine but also for other mucosal vaccines for enteric infections