Background Late-onset asthma (LOA) has distinct characteristics and its pathogenesis might rely on unique pathways. Although current studies are focused primarily on childhood asthma, more research is needed to show the mechanisms underlying LOA. Objective To conduct genomewide association analysis and gene-based analysis to identify single-nucleotide polymorphisms and genes associated with LOA. Methods The Women's Health Initiative (WHI) observational cohort and the Multi-Ethnic Study of Atherosclerosis (MESA) were used to identify subjects with LOA. The association between LOA and body mass index and smoking was evaluated. In the discovery stage of the genetic analysis, 1,218 African American subjects from WHI with genotype data (271 cases and 947 controls) were used for single-nucleotide polymorphism and gene-based association analyses. Significant or suggestive results were subsequently investigated in an independent African American population from MESA (38 cases and 806 controls). Results In WHI, the relative odds for LOA in obese vs normal-weight subjects was 2.55 (95% confidence interval 1.74–3.76). Ever smokers also had greater odds for LOA compared with never smokers (odds ratio 1.59, 95% confidence interval 1.21–2.09). The same trends were observed in MESA. In WHI, 6 single-nucleotide polymorphisms were associated with LOA at a genomewide-suggestive significance level (P < 1.0 × 10−5). The gene ZNF248 was associated with LOA and reached genomewide significance (P = 4.0 × 10−7). In MESA, the association between ZNF248 and LOA was successfully replicated (P =.015). Conclusion Smoking and obesity are risk factors for LOA. ZNF248 confers increased susceptibility to LOA in African Americans.