Genetic characterization of preschool wheeze phenotypes

Area of Science:

• Genetics
• Pediatrics
• Respiratory Medicine

Background:

• Preschool wheeze is a complex syndrome with unknown causes, hindering effective treatment and prevention.
• Current understanding of preschool wheeze's genetic underpinnings and disease mechanisms is limited.

Purpose of the Study:

• To elucidate the genetic susceptibility and disease mechanisms of preschool wheeze phenotypes.
• To conduct large-scale genome-wide association study (GWAS) analyses to identify genetic factors.

Main Methods:

• Performed meta-analyses of GWAS on early-onset wheeze and its subtypes (transient and persistent) in over 13,000 children.
• Utilized data from 15 discovery cohorts and replicated findings in 7 additional cohorts (up to 5,000 children).
• Assessed genetic overlap between preschool wheeze and adult asthma-related traits (atopy, eosinophils, lung function).

Main Results:

• Genome-wide significant association found for variants near the GSDMB gene with early-onset and persistent wheeze, but not transient wheeze.
• Other known asthma loci, including CDHR3, were associated with early-onset wheeze.
• Genetic risk for early-onset wheeze correlated with genetic risk for adult asthma, atopy, and lower lung function, primarily driven by persistent wheeze.

Conclusions:

• Preschool wheeze phenotypes exhibit distinct genetic associations and enrichments with asthma-related traits.
• These findings suggest different etiologies for wheeze phenotypes, potentially guiding optimized prevention and treatment strategies.