Genetic characterization of preschool wheeze phenotypes

Preschool wheeze is a heterogenous and poorly understood clinical syndrome. As a result, current treatments are insufficient, and prevention is not possible. To increase understanding of the genetic susceptibility and underlying disease mechanisms of wheeze phenotypes in early childhood through large-scale genome-wide association study (GWAS) analyses. We performed meta-analyses of GWAS on early-onset wheeze, defined as recurrent wheeze or asthma in the first 3 years of life, and subtypes hereof, including early transient and persistent wheeze, defined by asthma/wheeze at age 3 and subsequent remission or persistence at age 6 respectively. The discovery analyses included data on more than 13,000 children from 15 cohorts and replication was sought through meta-analyses of data from 7 additional cohorts including up to 5,000 children. Genetic variants associated with asthma-related traits in adulthood (adult asthma, atopy, eosinophils and lung function) were used to quantify the degree to which genetic risk influencing asthma-related adult traits also influences genetic risk of preschool wheeze. Variants near the GSDMB gene in the 17q-region showed genome-wide significant association with early onset (rs2305480, OR = 1.26 (1.17 - 1.33), P = 2.30E-16), and persistent (rs11078926, OR = 1.43 (1.30 - 1.578), P = 2.14E-11), but not with early transient wheeze (rs1054609, OR = 1.08 (0.98 - 1.18), P = 0.094). Other known asthma loci were associated with early onset wheeze, particularly CDHR3. Additionally, increased genetic risk to early onset wheeze was associated with genetic risk for asthma at older ages, atopy, eosinophil count and lower adult lung function. This was driven by persistent wheeze while transient early wheeze was only associated with low lung function. Preschool wheeze phenotypes displayed distinct patterns of single SNP associations and genetic enrichment with asthma related traits. These results indicate distinct etiologies of wheeze phenotypes, which could inform studies in optimization of prevention and treatment strategies.