Background Previously identified asthma-susceptibility genes account for a small part of asthma heritability and their role in asthma pathogenesis is unclear. We explored associations between genetic variants in the 17q21 locus, CDHR3 (cadherin-related family member 3) , coding a receptor for Rhinovirus-C, preschool wheeze and asthma at 7 years. Methods Four genetic variants in the 17q21 locus (rs8076131, rs12603332, rs8079416, rs3859192) and rs6967330 in CDHR3 were studied regarding associations with preschool wheeze and asthma at 7 years. We compared 125 cases, enrolled during an acute wheezing episode, with 96 healthy controls at preschool age (6-45 months). At 7 years cases with asthma (N=68) and without asthma (N=31) were compared regarding genetic variants and other clinical parameters. Results Rs8076131 (AA vs GG) was associated with preschool wheeze (OR 3.50, p=0.001), and asthma at 7 years (OR 8.55, p=0.002). Rs12603332 (CC vs TT) was related to asthma at 7 years irrespective of rhinovirus infection at inclusion or current signs of airborne allergy (aOR 7.17, p=0.016). The association of rs6967330 with asthma was restricted to children with specific genotypes in the 17q21 locus; rs8076131-AA (p=0.028) , rs8079416-CC (p=0.006), and rs3859192-TT (p=0.042). Rhinovirus infection at inclusion was significantly related to asthma exclusively in homozygotes rs8079416-CC (p=0.032) and rs3859192-TT (p=0.027). Conclusion Our results highlight the impact of asthma heritability by reporting strong associations between 17q21 locus and asthma in a high-risk cohort. The association of rs6967330 in CDHR3 and early-life rhinovirus infection with asthma at school age might be dependent on specific genotypes in the 17q21 locus.