BACKGROUND: Genome-wide association studies have identified associations of genetic variants at 17q21 near ORMDL3 with childhood asthma. OBJECTIVES: We sought to determine whether associations in this region are specific to particular asthma phenotypes and specific to ORMDL3. METHODS: We examined associations between 244 independent single nucleotide polymorphisms (SNPs) plus 13 previously identified asthma-related SNPs in the region between 34 and 36 Mb on chromosome 17 and early wheezing phenotypes, doctor-diagnosed asthma and atopy at 7½ years, and bronchial hyperresponsiveness and lung function at 8½ years in 7045 children from the Avon Longitudinal Study of Parents and Children birth cohort study. With this, cis expression quantitative trait loci signals for the same SNPs were assessed in 875 samples across genes in the same region. RESULTS: The strongest evidence for phenotypic association was seen for persistent wheezing (rs8076131 near ORMDL3: relative risk ratio [RRR], 1.60 [95% CI, 1.40-1.84], P = 1.4 × 10(-11); rs2305480 near GSDML: RRR, 1.60 [95% CI, 1.39-1.83], P = 1.5 × 10(-11); and rs9303277 near IKZF3: RRR, 1.57 [95% CI, 1.37-1.79], P = 4.4 × 10(-11)). Similar but less precisely estimated effects were seen for intermediate-onset wheeze, but there was little evidence of associations with other wheezing phenotypes. There was some evidence of associations with bronchial hyperresponsiveness. SNPs across the whole region show strong evidence of association with differential levels of expression at GSDML, IKZF3, and MED24, as well as ORMDL3. CONCLUSIONS: Associations of SNPs in the 17q21 locus are specific to asthma and specific wheezing phenotypes and are not explained by associations with intermediate phenotypes, such as atopy or lung function.