Genetic factors, stressors operating over the life course, and various aspects of social context have been shown to play a role in the etiology of depressive symptoms. However, empirical studies that investigate environmental and genetic factors, as well as their interactions, remain rare. First, traditional genetic analysis methods were employed to investigate the genetic determinants of depressive symptoms at the single-nucleotide polymorphism (SNP) level, incorporating different approaches to analyzing longitudinal outcomes (baseline measure, measures averaged over exam visits, and a repeated measures); secondly, state-of-the-art genomic region-level analysis methods were utilized to identify genomic regions associated with depressive symptoms; and finally, genomic region by environment (G x E) analysis methods were used to examine of the extent to which individual- and neighborhood-level social exposures modify the genetic effects of depressive symptoms. All analyses were performed both within and across multiple ethnicities (African, European, Hispanic, and Chinese Americans). This work includes evidence that incorporating longitudinal measures (through the averaged or repeated measures approach) results in smaller p-values and an increase in the number of single-nucleotide polymorphisms (SNP) reaching genome-wide suggestive level, as well as both genomic-region determinants of depressive symptom scores and modification of those regions by social environments at both an individual- and neighborhood-level (chronic burden, social support, or neighborhood index score). This dissertation represents an important contribution to life sciences in several ways: first, this is the first analysis that incorporates novel methods with depressive symptom outcomes; second, through the investigation of the association of genetic variants and depressive symptoms across multiple ethnicities; third, through a detailed comparison of how longitudinal data can be used to define a mental health phenotypes in the context of genetic studies; and finally through the use of both individual- and neighborhood-level interactions with genetic information at both an individual SNP level and a region level. Replicating these initial findings in other studies will help motivate efforts to reduce depressive symptom burden through modifiable environmental factors in individuals with certain genetic profiles.