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BACKGROUND: Asthma and recurrent wheeze in the first years of life represent a heterogenous and poorly understood syndrome with a need to understand to which extent phenotypes reflect distinct underlying mechanisms.OBJECTIVE: To investigate if specific genetic asthma mechanisms, represented by genetic risk loci, are associated with specific disease courses and asthma phenotypes.METHODS: Known childhood asthma risk loci (GSDMB, CDHR3, FUT2, ABO, HLA-DQA1, IL33, IL1RL1, IL13, and TSLP) were analyzed in relation to redeemed prescriptions for asthma and allergy medication from birth to age 15 years in more than 23,000 children from the iPSYCH study. Gene variants were studied separately and as combined scores based on putative similar mechanisms. Association with atopic and non-atopic asthma phenotypes was examined in more than 6,000 children from the COPSAC, BAMSE and CHILD birth cohorts.RESULTS: GSDMB and CDHR3 were the strongest risk loci for asthma prescriptions in the first years of life with effects continuing into school-age, although with attenuating effect size. CDHR3 was characterized by associations present already in the first year of life and a strong interaction with GSDMB genotype. Suspected T2-related loci were characterized by a slightly later onset around 2-3 years of age with increasing or stable effect size to age 15, and increased risk of allergic rhinitis. Only GSDMB and CDHR3 were associated with early transient disease while most loci were associated with both persistent and late-onset disease and with both atopic and non-atopic asthma.CONCLUSION: Risk loci of early childhood asthma seem to involve different disease mechanisms as illustrated by their specific age-related effects. However, risk loci generally showed associations across classical age- and atopy-related phenotypes, suggesting that specific asthma mechanisms are not well captured by classical phenotyping.