Lactose, a sugar in ruminant animal milk, is broken down by the enzyme lactase in the small intestine. Most humans lose their ability to digest lactose after weaning, when lactase production decreases; this trait is called lactase non-persistence (LNP). Others, however, carry the lactase persistence (LP) trait, in which they maintain high levels of lactase into adulthood. The LP trait is caused by variants that regulate the expression of the lactase-coding gene, LCT. Four known causal variants for LP are found in African populations, primarily in those with a history of pastoralism. In Africa, genetic ancestry, migration patterns, and subsistence methods are heavily correlated with language. There have been two expansions of pastoralism into eastern Africa: an initial expansion of pastoralist groups speaking Afroasiatic languages, and a second expansion of pastoralist groups speaking Nilo-Saharan languages. In this study, we aimed to evaluate the relationship between LP and pastoralism, assess genotype-phenotype relationships, and identify additional causal variants for LP. We collected DNA samples, lactose tolerance testing results, and demographic data from n = 878 study participants. First, we created boxplots to assess variation in the LP phenotype between various populations. Second, we created boxplots, performed multiple linear regressions, and simple linear regressions to evaluate the relationship between different genotypes and variation in the LP trait expression. Finally, we conducted a genome-wide association study to identify variants significantly associated with LP, and we also identified variants that were associated epistatically with known causal variants for LP. We then evaluated putative LP-associated variants for overlap with gene-regulatory regions and proximity to genes with functions related to lactose and glucose metabolism. As expected, groups of pastoralist populations and groups of individuals carrying known causal variants for LP tended to have a greater prevalence of LP. Interestingly, pastoralist Afroasiatic-speaking groups tended to have a greater prevalence of LP than pastoralist Nilo-Saharan-speaking groups. Additionally, individuals carrying some of the known causal variants for LP more common in Afro-Asiatic speaking groups tended to have a greater prevalence of LP compared to individuals carrying the other known causal variants for LP. Furthermore, the number of different variants causal for LP that an individual carried had a significant, positive correlation with greater measures of LP in that individual, when accounting for age, sex, and population. We identified potentially causal variants for both lactose digestion and blood glucose homeostasis.

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