Genome-wide association studies have been extensively used to identify genetic factors contributing to complex traits, but the variants identified thus far explain a small portion of the heritabilities of these traits. In my dissertation, I aimed to understand the role of rare variation in complex traits and identify host genotype influences on the microbiome, two understudied components of complex trait genetics. I studied rare variation in two separate studies. First, I searched for contributions from rare and low frequency putatively functional variants on asthma pathogenesis in a large sample of ethnically diverse populations (the EVE Consortium of Asthma Genetics). The few associations detected in this study were limited to single ethnic groups, suggesting that rare or low frequency variants that influence asthma are likely to be ethnic specific. Our results also indicate that rare and low frequency loss-of-function variants nearby coding regions are unlikely to explain a significant portion of the heritability for asthma. Second, I studied the effects of rare variants on blood lipid traits (LDL cholesterol, LDL cholesterol, triglycerides and total cholesterol) in the Hutterites, a founder population of European descent. I tested the genome-wide effects of variants that are absent or rare variants in Europeans but have drifted to higher frequencies in the Hutterites. I identified four novel variants associated with LDL-C or HDL-C, two of which were also at novel loci, and in addition replicated a known splicing variant in APOC3. Our results suggested that rare non-coding risk variants are likely to mediate their effects through gene expression. Lastly, I studied the upper airway microbiome, which has been associated with respiratory diseases, in the Hutterites. I identified airway bacteria whose abundance is influenced by host genotype and determined that host expression of innate and mucosal immune pathway genes plays a central role in structuring the airway microbiome (three results tables for the microbiome study are available online in supplementary files).