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 L. 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 journalArticle

1 Citation (Scopus)

Abstract

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
Volume19
Issue number1
DOIs
StatePublished - Oct 20 2018

Fingerprint

Exome
Bronchopulmonary Dysplasia
Gene Regulatory Networks
Premature Birth
Extremely Premature Infants
Genes
Neuregulins
Morbidity
Cyclic AMP-Dependent Protein Kinases
Epidermal Growth Factor Receptor
Premature Infants
Lung Diseases
Genome
Phenotype
Gene Expression

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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

In: BMC Genetics, Vol. 19, No. 1, 94, 20.10.2018.

Research output: Contribution to journalArticle

Hamvas, A, Feng, R, Bi, Y, Wang, F, Bhattacharya, S, Mereness, J, Kaushal, M, Cotten, CM, Ballard, PL, Mariani, TJ, Alexander, B, Chougnet, C, Gratton, T, Greenberg, JM, Grisby, C, Hardie, W, Jobe, AH, Koch, B, McDowell, K, Thornton, K, Bates, P, Cleveland, C, Ferkol, T, Hoffmann, J, Holland, MR, Kemp, J, Levy, PT, Linneman, L, Sicard-Su, J, Simpson, G, Singh, GK, Warner, B, Ballard, PL, Ballard, RA, Durand, DJ, Eichenwald, EC, Keller, RL, Khan, AM, Lusk, L, Merrill, JD, Nielson, DW, Rogers, EE, Asselin, JM, Balan, S, Burson, K, Chapin, C, Josiah-Davis, E, Garcia, C, Horneman, H, Hinojosa, R, Johnson, C, Kelley, S, Knowles, KL, Layne Lillie, M, Martin, K, Martin, S, Arldt-Mcalister, J, McDavid, GE, Pacello, L, Rodgers, S, Sperry, DK, Aschner, JL, Beller, AB, Fike, C, Guthrie, S, Hartert, T, Maitre, N, Moore, P, Hunt, MO, Rogers, TJ, Settles, OL, Steele, S, Summar, M, Wadley, S, D'Angio, C, Kumar, V, Mariani, T, Pryhuber, G, Ren, C, Reynolds, AM, Ryan, RM, Scheible, K, Stevens, T, Huyck, H, Lunger, V, Castiglione, S, Horan, A, Maffet, D, O'Donnell, J, Sacilowski, M, Scalise, T, Werner, E, Zayac, J, Bordeaux, K, Brown, P, Epping, J, Flattery-Walsh, L, Germuga, D, Jenks, N, Platt, M, Popplewell, E, Prentice, S, Ciccio, K, Cotten, M, Fisher, K, Sharp, J & Voynow, JA 2018, 'Exome sequencing identifies gene variants and networks associated with extreme respiratory outcomes following preterm birth', BMC Genetics, vol. 19, no. 1, 94. https://doi.org/10.1186/s12863-018-0679-7
Hamvas, Aaron ; Feng, Rui ; Bi, Yingtao ; Wang, Fan ; Bhattacharya, Soumyaroop ; Mereness, Jared ; Kaushal, Madhurima ; Cotten, C. Michael ; Ballard, Philip L. ; Mariani, Thomas J. ; Alexander, Barbara ; Chougnet, Claire ; Gratton, Tari ; Greenberg, James M. ; Grisby, Cathy ; Hardie, William ; Jobe, Alan H. ; Koch, Beth ; McDowell, Karen ; Thornton, Kelly ; Bates, Pamela ; Cleveland, Claudia ; Ferkol, Thomas ; Hoffmann, Julie ; Holland, Mark R. ; Kemp, James ; Levy, Philip T. ; Linneman, Laura ; Sicard-Su, Jayne ; Simpson, Gina ; Singh, Gautam K. ; Warner, Barbara ; Ballard, Philip L. ; Ballard, Roberta A. ; Durand, David J. ; Eichenwald, Eric C. ; Keller, Roberta L. ; Khan, Amir M. ; Lusk, Leslie ; Merrill, Jeffrey D. ; Nielson, Dennis W. ; Rogers, Elizabeth E. ; Asselin, Jeanette M. ; Balan, Samantha ; Burson, Katrina ; Chapin, Cheryl ; Josiah-Davis, Erna ; Garcia, Carmen ; Horneman, Hart ; Hinojosa, Rick ; Johnson, Christopher ; Kelley, Susan ; Knowles, Karin L. ; Layne Lillie, M. ; Martin, Karen ; Martin, Sarah ; Arldt-Mcalister, Julie ; McDavid, Georgia E. ; Pacello, Lori ; Rodgers, Shawna ; Sperry, Daniel K. ; Aschner, Judy L. ; Beller, Amy B. ; Fike, Candice ; Guthrie, Scott ; Hartert, Tina ; Maitre, Nathalie ; Moore, Paul ; Hunt, Mark O. ; Rogers, Theresa J. ; Settles, Odessa L. ; Steele, Steven ; Summar, Marshall ; Wadley, Sharon ; D'Angio, Carl ; Kumar, Vasanth ; Mariani, Tom ; Pryhuber, Gloria ; Ren, Clement ; Reynolds, Anne Marie ; Ryan, Rita M. ; Scheible, Kristin ; Stevens, Timothy ; Huyck, Heidie ; Lunger, Valerie ; Castiglione, Shannon ; Horan, Aimee ; Maffet, Deanna ; O'Donnell, Jane ; Sacilowski, Michael ; Scalise, Tanya ; Werner, Elizabeth ; Zayac, Jason ; Bordeaux, Kim ; Brown, Pam ; Epping, Julia ; Flattery-Walsh, Lisa ; Germuga, Donna ; Jenks, Nancy ; Platt, Mary ; Popplewell, Eileen ; Prentice, Sandra ; Ciccio, Kim ; Cotten, Michael ; Fisher, Kim ; Sharp, Jack ; Voynow, Judith A. / Exome sequencing identifies gene variants and networks associated with extreme respiratory outcomes following preterm birth. In: BMC Genetics. 2018 ; Vol. 19, No. 1.
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abstract = "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.",
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T1 - Exome sequencing identifies gene variants and networks associated with extreme respiratory outcomes following preterm birth

AU - Hamvas, Aaron

AU - Feng, Rui

AU - Bi, Yingtao

AU - Wang, Fan

AU - Bhattacharya, Soumyaroop

AU - Mereness, Jared

AU - Kaushal, Madhurima

AU - Cotten, C. Michael

AU - Ballard, Philip L.

AU - Mariani, Thomas J.

AU - Alexander, Barbara

AU - Chougnet, Claire

AU - Gratton, Tari

AU - Greenberg, James M.

AU - Grisby, Cathy

AU - Hardie, William

AU - Jobe, Alan H.

AU - Koch, Beth

AU - McDowell, Karen

AU - Thornton, Kelly

AU - Bates, Pamela

AU - Cleveland, Claudia

AU - Ferkol, Thomas

AU - Hoffmann, Julie

AU - Holland, Mark R.

AU - Kemp, James

AU - Levy, Philip T.

AU - Linneman, Laura

AU - Sicard-Su, Jayne

AU - Simpson, Gina

AU - Singh, Gautam K.

AU - Warner, Barbara

AU - Ballard, Philip L.

AU - Ballard, Roberta A.

AU - Durand, David J.

AU - Eichenwald, Eric C.

AU - Keller, Roberta L.

AU - Khan, Amir M.

AU - Lusk, Leslie

AU - Merrill, Jeffrey D.

AU - Nielson, Dennis W.

AU - Rogers, Elizabeth E.

AU - Asselin, Jeanette M.

AU - Balan, Samantha

AU - Burson, Katrina

AU - Chapin, Cheryl

AU - Josiah-Davis, Erna

AU - Garcia, Carmen

AU - Horneman, Hart

AU - Hinojosa, Rick

AU - Johnson, Christopher

AU - Kelley, Susan

AU - Knowles, Karin L.

AU - Layne Lillie, M.

AU - Martin, Karen

AU - Martin, Sarah

AU - Arldt-Mcalister, Julie

AU - McDavid, Georgia E.

AU - Pacello, Lori

AU - Rodgers, Shawna

AU - Sperry, Daniel K.

AU - Aschner, Judy L.

AU - Beller, Amy B.

AU - Fike, Candice

AU - Guthrie, Scott

AU - Hartert, Tina

AU - Maitre, Nathalie

AU - Moore, Paul

AU - Hunt, Mark O.

AU - Rogers, Theresa J.

AU - Settles, Odessa L.

AU - Steele, Steven

AU - Summar, Marshall

AU - Wadley, Sharon

AU - D'Angio, Carl

AU - Kumar, Vasanth

AU - Mariani, Tom

AU - Pryhuber, Gloria

AU - Ren, Clement

AU - Reynolds, Anne Marie

AU - Ryan, Rita M.

AU - Scheible, Kristin

AU - Stevens, Timothy

AU - Huyck, Heidie

AU - Lunger, Valerie

AU - Castiglione, Shannon

AU - Horan, Aimee

AU - Maffet, Deanna

AU - O'Donnell, Jane

AU - Sacilowski, Michael

AU - Scalise, Tanya

AU - Werner, Elizabeth

AU - Zayac, Jason

AU - Bordeaux, Kim

AU - Brown, Pam

AU - Epping, Julia

AU - Flattery-Walsh, Lisa

AU - Germuga, Donna

AU - Jenks, Nancy

AU - Platt, Mary

AU - Popplewell, Eileen

AU - Prentice, Sandra

AU - Ciccio, Kim

AU - Cotten, Michael

AU - Fisher, Kim

AU - Sharp, Jack

AU - Voynow, Judith A.

PY - 2018/10/20

Y1 - 2018/10/20

N2 - 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.

AB - 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.

KW - Bronchopulmonary dysplasia (BPD)

KW - Prematurity and respiratory outcomes program (PROP)

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