Nematode parasites show a characteristic aggregated distribution among hosts. This observation has important implications for pathogenesis, immunology, and control of these infections, but the relative roles of environment and genetics in determining these patterns have remained uncertain. This paper presents the results of the first genome scan for susceptibility to infection with roundworm (Ascaris lumbricoides). Data on 375 genetic markers were generated for each of 444 members of a genetically isolated Nepalese population, the Jirels. Ascaris worm burden as assessed by egg counts was measured in these same individuals by using the Kato Katz thick smear method. The extensive genealogical data available for the population allowed assignment of all 444 individuals to a single pedigree that contained 6,209 pairs of relatives that were informative for genetic analysis. A variance components linkage analysis resulted in the unequivocal localization of two genes (one on chromosome 1 and another on chromosome 13) with clear, significant effects on susceptibility to Ascaris infection. This is the first evidence that individual quantitative trait loci influence variation in Ascaris burden in humans.

Abstract. Epidemiologic studies of helminthic infections have shown that susceptibility to these parasites frequently aggregates in families, suggesting the possible involvement of genetic factors. This paper presents a genetic epidemiologic analysis of Ascaris lumbricoides infection in the Jirel population of eastern Nepal. A total of 1,261 individuals belonging to a single pedigree were assessed for intensity of Ascaris infection at two time points. Following an initial assessment in which all individuals were treated with albendazole, a follow-up examination was performed one year later to evaluate reinfection patterns. Three measures of worm burden were analyzed, including eggs per gram of feces, direct worm counts, and worm biomass (weight). For all traits, variance component analysis of the familial data provided unequivocal evidence for a strong genetic component accounting for between 30% and 50% of the variation in worm burden. Shared environmental (i.e., common household) effects account for between 3% and 13% of the total phenotypic variance.

A linkage-based genome scan of 1,258 members of a single pedigree of the Jirel population of Nepal localized 6 potential quantitative trait loci (QTLs) influencing susceptibility to infection with Ascaris lumbricoides, the most common soil-transmitted intestinal helminth. Three QTLs exhibited genomewide significance, including QTLs on chromosomes 13 (logarithm of the odds ratio [LOD] score, 3.37; genomewide P = .013, 8 (LOD score, 3.03; genomewide P = .031), and 11 (LOD score, 3.19; genomewide P = .020). Another QTL on chromosome 1 approached significance (LOD score, 2.72; genomewide P = .067). There was suggestive evidence of linkage for 2 additional loci on chromosomes 1 and 13.

Macroparasite infections (e.g., helminths) remain a major human health concern. However, assessing transmission dynamics is problematic because the direct observation of macroparasite dispersal among hosts is not possible. We used a novel landscape genetics approach to examine transmission of the human roundworm Ascaris lumbricoides in a small human population in Jiri, Nepal. Unexpectedly, we found significant genetic structuring of parasites, indicating the presence of multiple transmission foci within a small sampling area (∼14 km2). We analyzed several epidemiological variables, and found that transmission is spatially autocorrelated around households and that transmission foci are stable over time despite extensive human movement. These results would not have been obtainable via a traditional epidemiological study based on worm counts alone. Our data refute the assumption that a single host population corresponds to a single parasite transmission unit, an assumption implicit in many classic models of macroparasite transmission. Newer models have shown that the metapopulation-like pattern observed in our data can adversely affect targeted control strategies aimed at community-wide impacts. Furthermore, the observed metapopulation structure and local mating patterns generate an excess of homozygotes that can accelerate the spread of recessive traits such as drug resistance. Our study illustrates how molecular analyses complement traditional epidemiological information in providing a better understanding of parasite transmission. Similar landscape genetic approaches in other macroparasite systems will be warranted if an accurate depiction of the transmission process is to be used to inform effective control strategies.