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Multicohort analysis unveils axon guidance pathways linking small for gestational age to spirometric restriction

James F Read1, Debra A Stern2, Tara F Carr2

  • 1Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA. jread@arizona.edu.

Nature Communications
|May 2, 2026
PubMed

Insights

Children born small for gestational age (SGA) have higher risks for chronic diseases. A distinct molecular endotype involving axon guidance proteins is linked to later-life lung function in SGA children.

Area of Science:

  • Genetics
  • Developmental Biology
  • Pulmonology

Background:

  • Children born small for gestational age (SGA) have increased risks for metabolic, cardiovascular, respiratory, and neurodevelopmental disorders, and premature mortality.
  • The underlying biological mechanisms contributing to these long-term health issues in SGA individuals are not fully understood.

Purpose of the Study:

  • To identify molecular pathways associated with being born small for gestational age (SGA) and subsequent lung function.
  • To investigate the role of axon guidance pathways in the developmental origins of chronic disease.

Main Methods:

  • Analysis of blood proteomic data from multiple birth cohorts.
  • Correlation of proteomic findings with spirometric lung function data.
  • Genome-wide association studies (GWAS) and an experimental sheep model to validate genetic associations.

Main Results:

  • Approximately one-third of SGA children displayed a unique molecular endotype characterized by dysregulated axon guidance proteins in cord blood.
  • These axon guidance proteins were inversely associated with spirometric restriction in peripheral blood later in life.
  • Convergent evidence from GWAS and a sheep model indicated that axon guidance genes are significantly associated with lung function indices (FEV1/FVC) and are widely expressed during fetal development.

Conclusions:

  • Axon guidance pathways are implicated in a distinct molecular endotype observed in some SGA children.
  • These pathways are linked to lung function deficits and may contribute to multiorgan morbidity, offering potential therapeutic targets.

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