Exome sequencing identifies gene variants and networks associated with extreme respiratory outcomes following preterm birth

Aaron Hamvas, Rui Feng, Yingtao Bi, Fan Wang, Soumyaroop Bhattacharya, Jared Mereness, Madhurima Kaushal, C. Michael Cotten, Philip L. Ballard, Thomas J. Mariani, Barbara Alexander, Claire Chougnet, Tari Gratton, James M. Greenberg, Cathy Grisby, William Hardie, Alan H. Jobe, Beth Koch, Karen McDowell, Kelly ThorntonPamela Bates, Claudia Cleveland, Thomas Ferkol, Julie Hoffmann, Mark R. Holland, James Kemp, Philip T. Levy, Laura Linneman, Jayne Sicard-Su, Gina Simpson, Gautam K. Singh, Barbara Warner, Philip L. Ballard, Roberta A. Ballard, David J. Durand, Eric C. Eichenwald, Roberta L. Keller, Amir M. Khan, Leslie Lusk, Jeffrey D. Merrill, Dennis W. Nielson, Elizabeth E. Rogers, Jeanette M. Asselin, Samantha Balan, Katrina Burson, Cheryl Chapin, Erna Josiah-Davis, Carmen Garcia, Hart Horneman, Rick Hinojosa, Christopher Johnson, Susan Kelley, Karin L. Knowles, M. Layne Lillie, Karen Martin, Sarah Martin, Julie Arldt-Mcalister, Georgia E. McDavid, Lori Pacello, Shawna Rodgers, Daniel K. Sperry, Judy Aschner, Amy B. Beller, Candice Fike, Scott Guthrie, Tina Hartert, Nathalie Maitre, Paul Moore, Mark O. Hunt, Theresa J. Rogers, Odessa L. Settles, Steven Steele, Marshall Summar, Sharon Wadley, Carl D'Angio, Vasanth Kumar, Tom Mariani, Gloria Pryhuber, Clement Ren, Anne Marie Reynolds, Rita M. Ryan, Kristin Scheible, Timothy Stevens, Heidie Huyck, Valerie Lunger, Shannon Castiglione, Aimee Horan, Deanna Maffet, Jane O'Donnell, Michael Sacilowski, Tanya Scalise, Elizabeth Werner, Jason Zayac, Kim Bordeaux, Pam Brown, Julia Epping, Lisa Flattery-Walsh, Donna Germuga, Nancy Jenks, Mary Platt, Eileen Popplewell, Sandra Prentice, Kim Ciccio, Michael Cotten, Kim Fisher, Jack Sharp, Judith A. Voynow

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Background: Previous studies have identified genetic variants associated with bronchopulmonary dysplasia (BPD) in extremely preterm infants. However, findings with genome-wide significance have been rare, and not replicated. We hypothesized that whole exome sequencing (WES) of premature subjects with extremely divergent phenotypic outcomes could facilitate the identification of genetic variants or gene networks contributing disease risk. Results: The Prematurity and Respiratory Outcomes Program (PROP) recruited a cohort of > 765 extremely preterm infants for the identification of markers of respiratory morbidity. We completed WES on 146 PROP subjects (85 affected, 61 unaffected) representing extreme phenotypes of early respiratory morbidity. We tested for association between disease status and individual common variants, screened for rare variants exclusive to either affected or unaffected subjects, and tested the combined association of variants across gene loci. Pathway analysis was performed and disease-related expression patterns were assessed. Marginal association with BPD was observed for numerous common and rare variants. We identified 345 genes with variants unique to BPD-affected preterm subjects, and 292 genes with variants unique to our unaffected preterm subjects. Of these unique variants, 28 (19 in the affected cohort and 9 in unaffected cohort) replicate a prior WES study of BPD-associated variants. Pathway analysis of sets of variants, informed by disease-related gene expression, implicated protein kinase A, MAPK and Neuregulin/epidermal growth factor receptor signaling. Conclusions: We identified novel genes and associated pathways that may play an important role in susceptibility/resilience for the development of lung disease in preterm infants.

Original languageEnglish (US)
Article number94
JournalBMC genetics
Issue number1
StatePublished - Oct 20 2018


  • Bronchopulmonary dysplasia (BPD)
  • Prematurity and respiratory outcomes program (PROP)

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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