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Background: Individuals genetically susceptible to high schistosomiasis worm burden may contribute disproportionately to transmission and could be prioritized for control. Identifying genes involved may guide development of therapy. Methodology/Principal findings: A cohort of 606 children aged 10–15 years were recruited in the Albert Nile region of Uganda and assessed for Schistosoma mansoni worm burden using the Up-Converting Particle Lateral Flow (UCP-LF) test detecting circulating anodic antigen (CAA), point-of-care Circulating Cathodic Antigen (POC-CCA) and Kato-Katz tests. Whole genome genotyping was conducted on 326 children comprising the top and bottom 25% of worm burden. Linear models were fitted to identify variants associated with worm burden in preselected candidate genes. Expression quantitative trait locus (eQTL) analysis was conducted for candidate genes with UCP-LF worm burden included as a covariate. Single Nucleotide Polymorphism loci associated with UCP-LF CAA included IL6 rs2066992 (OR = 0.43, p = 0.0006) and rs7793163 (OR = 2.0, p = 0.0007); IL21 SNP kgp513476 (OR 1.79, p = 0.0025) and IL17B SNP kgp708159 (OR = 0.35, p = 0.0028). A haplotype in the IL10 locus was associated with lower worm burden (OR = 0.53, p = 0.015) and overlapped SNPs rs1800896, rs1800871 and rs1800872. Significant haplotypes (p<0.05, overlapping significant SNP) associated with worm burden were observed in IL6 and the Th17 pathway IL12B and IL17B genes. There were significant eQTL in the IL6, IL5, IL21, IL25 and IFNG regions. Conclusions: Variants associated with S. mansoni worm burden were in IL6, FCN2, RNASE3, IL10, IL12B and IL17B gene loci. However only eQTL associations remained significant after Bonferroni correction. In summary, immune balance, pathogen recognition and Th17 pathways may play a role in modulating Schistosoma worm burden. Individuals carrying risk variants may be targeted first in allocation of control efforts to reduce the burden of schistosomiasis in the community. Author summary: This study investigated genetic risk factors for high worm burden in a cohort of 606 children aged 10–15 years old in the Albert Nile region of Uganda. Genotyping was conducted on 326 children who comprised the top and bottom 25% of worm burden. Results showed single nucleotide polymorphisms (SNPs) associated with worm burden in the IL6, IL21 and IL17B genes, and a haplotype in the IL10 locus associated with lower worm burden. Expression quantitative trait locus (eQTL) analysis revealed significant gene and worm burden associations in the IL6 region, and expression associations in the IL5, IL21, IL25 and IFNG loci. These findings suggest that immune balance, pathogen recognition and Th17 pathways may be involved in modulating Schistosoma worm burden and that individuals carrying risk variants may be prioritized to improve control efforts. [ABSTRACT FROM AUTHOR]