This dissertation examines gene-environment relationships in diverse populations around the globe and provides novel insight regarding genetic and environmental susceptibility to human disease. Using three arsenic-exposed cohorts from diverse ancestral and environmental backgrounds, we estimate the impact of rare, protein-coding variation in the arsenic methyltransferase (AS3MT) gene on arsenic metabolism efficiency (AME) and identify population-specific and shared causal rare variants. Because genetic variants affecting AME are expected to influence internal dose of arsenic, they can be used as instrumental variables (i.e. proxies) in order to assess the effect of arsenic dose/exposure on disease risk, an approach known as “Mendelian randomization” (MR). Here, we utilize genetic determinants of AME in a Bangladeshi cohort to obtain a MR-based estimate the effect of AME on hypertension risk, a relationship that remains an area of debate due to inconsistent findings in prior studies. Finally, to elucidate whether the effect of inherited prostate cancer (PCa) risk loci on biological mechanisms underlying PCa disparities differ between African American (AA) and European American (EA) men, we examine the effect of PCa risk loci on DNA methylation features of AA and EA benign and tumor PCa tissue.