Human growth is associated with distinct patterns of gene expression in evolutionarily conserved networks
Open accessAbstract
BACKGROUND: A co-ordinated tissue-independent gene expression profile associated with growth is present in rodent models and this is hypothesised to extend to all mammals. Growth in humans has similarities to other mammals but the return to active long bone growth in the pubertal growth spurt is a distinctly human growth event. The aim of this study was to describe gene expression and biological pathways associated with stages of growth in children and to assess tissue-independent expression patterns in relation to human growth. RESULTS: We conducted gene expression analysis on a library of datasets from normal children with age annotation, collated from the NCBI Gene Expression Omnibus (GEO) and EBI Arrayexpress databases. A primary data set was generated using cells of lymphoid origin from normal children; the expression of 688 genes (ANOVA false discovery rate modified p-value, q < 0.1) was associated with age, and subsets of these genes formed clusters that correlated with the phases of growth--infancy, childhood, puberty and final height. Network analysis on these clusters identified evolutionarily conserved growth pathways (NOTCH, VEGF, TGFB, WNT and glucocorticoid receptor--Hyper-geometric test, q < 0.05). The greatest degree of network 'connectivity' and hence functional significance was present in infancy (Wilcoxon test, p < 0.05), which then decreased through to adulthood. These observations were confirmed in a separate validation data set from lymphoid tissue. Similar biological pathways were observed to be associated with development-related gene expression in other tissues (conjunctival epithelia, temporal lobe brain tissue and bone marrow) suggesting the existence of a tissue-independent genetic program for human growth and maturation. CONCLUSIONS: Similar evolutionarily conserved pathways have been associated with gene expression and child growth in multiple tissues. These expression profiles associate with the developmental phases of growth including the return to active long bone growth in puberty, a distinctly human event. These observations also have direct medical relevance to pathological changes that induce disease in children. Taking into account development-dependent gene expression profiles for normal children will be key to the appropriate selection of genes and pathways as potential biomarkers of disease or as drug targets.
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In growth from child to adult, serum albumin concentration is normal but low rising to adult normal, and VEGF is increased.
“Growth from child to adult | N ↓ rising to adult N | NA | NA | NA | NA | NA | ↑37, 38 , 161 | Connectivity VEGF gene‐metabolic pathway stronger in children”
From Hypoalbuminemia: Pathogenesis and Clinical Significance (2019) · cites this paper as [37]
The Results section reports a positive correlation between VEGFA gene-expression changes and the late-childhood/puberty growth phase, and the Discussion reports greater gene-network connectivity in infancy than at final height. These findings concern gene expression and network connectivity, not measured VEGF concentrations. The paper does not support the claim about serum albumin rising to adult-normal levels. (LLM, conf=0.84)
Experimental — accuracy not yet measuredVEGF expression and increased vascular permeability occur in infection, trauma, during fetal and postnatal growth, preparing for lactation, cancer, protein-losing enteropathy, and nephrotic syndrome.
“VEGF expression and increased vascular permeability occur in infection,14, 35 trauma,15, 16, 36 during fetal and postnatal growth,29, 37, 38, 39 preparing for lactation,39, 40 cancer,41, 42 protein‐losing enteropathy,43 and nephrotic syndrome44, 45 (Table 1).”
From Hypoalbuminemia: Pathogenesis and Clinical Significance (2019) · cites this paper as [37]
The Results (page unavailable) identify VEGFA expression changes and VEGF signalling pathways associated with childhood growth, supporting the postnatal-growth portion of the cited clause. The paper does not establish increased vascular permeability during growth or address fetal growth; the other conditions in the sentence have separate citations. (LLM, conf=0.86)
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Hypoalbuminemia: Pathogenesis and Clinical Significance
Soeters, P. B., Wolfe, R. R., & Shenkin, A. (2019) · Journal of Parenteral and Enteral Nutrition · doi:10.1002/jpen.1451 · Cited by 1,448 · see citing works
Bogin, B. A., Varea, C., Hermanussen, M., & Scheffler, C. (2018) · American Journal of Physical Anthropology · doi:10.1002/ajpa.23357 · Cited by 62 · see citing works
The Pediatric Cell Atlas: Defining the Growth Phase of Human Development at Single-Cell Resolution
Taylor, D. M., Aronow, B. J., Tan, K., Bernt, K. M., Salomonis, N., Greene, C. S., Frolova, A., Henrickson, S. E., Wells, A. D., Pei, L., et al. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.03.001 · Cited by 61 · see citing works
Characterization of GPR101 transcript structure and expression patterns
Trivellin, G., Bjelobaba, I. M., Daly, A., Larco, D. O., Palmeira, L., Faucz, F. R., Thiry, A., Leal, L. F., Rostomyan, L., Quezado, M., et al. (2016) · Journal of Molecular Endocrinology · doi:10.1530/jme-16-0045 · Cited by 46 · see citing works
Puig-Oliveras, A., Ballester, M., Corominas, J., Revilla, M., Estellé, J., Fernández, A. I., Ramayo‐Caldas, Y., & Folch, J. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0114862 · Cited by 40 · see citing works
Pharmacogenomics in Pediatric Oncology: Review of Gene—Drug Associations for Clinical Use
Mlakar, V., Huezo-Diaz, P., Uppugunduri, C. R. S., Krajinović, M., & Ansari, M. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17091502 · Cited by 40 · see citing works
Sex, Sport, IGF-1 and the Community Effect in Height Hypothesis
Bogin, B. A., Hermanussen, M., Blum, W. F., & Aßmann, C. (2015) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph120504816 · Cited by 37 · see citing works
Network analysis: a new approach to study endocrine disorders
Stevens, A., Leonibus, C. D., Hanson, D., Dowsey, A. W., Whatmore, A. J., Meyer, S., Donn, R. P., Chatelain, P., Banerjee, I., Cosgrove, K. E., et al. (2013) · Journal of Molecular Endocrinology · doi:10.1530/jme-13-0112 · Cited by 37 · see citing works
Self-citationLiu, H., Nguyen, Y., Nettleton, D. S., Dekkers, J. C. M., & Tuggle, C. K. (2016) · BMC Genomics · doi:10.1186/s12864-016-2395-x · Cited by 36 · see citing works
Transcriptomics and machine learning predict diagnosis and severity of growth hormone deficiency
Murray, P. G., Stevens, A., Leonibus, C. D., Koledova, E. B., Chatelain, P., & Clayton, P. (2018) · JCI Insight · doi:10.1172/jci.insight.93247 · Cited by 29 · see citing works
Self-citationStevens, A., Bonshek, C., Whatmore, A. J., Butcher, I., Hanson, D., Leonibus, C. D., Shaikh, M. G., Brown, M., O’Shea, E., Victor, S., et al. (2014) · The Pharmacogenomics Journal · doi:10.1038/tpj.2014.4 · Cited by 26 · see citing works
Self-citationPharmacogenomics in Pediatric Oncology: Mitigating Adverse Drug Reactions While Preserving Efficacy
Elzagallaai, A. A., Carleton, B., & Rieder, M. J. (2020) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-031320-104151 · Cited by 26 · see citing works
Leonibus, C. D., Chatelain, P., Knight, C., Clayton, P., & Stevens, A. (2015) · The Pharmacogenomics Journal · doi:10.1038/tpj.2015.67 · Cited by 21 · see citing works
Self-citationPediatric Perspective on Pharmacogenomics
Stevens, A., Leonibus, C. D., Hanson, D., Whatmore, A. J., Murray, P. G., Donn, R. P., Meyer, S., Chatelain, P., & Clayton, P. (2013) · Pharmacogenomics · doi:10.2217/pgs.13.193 · Cited by 20 · see citing works
Self-citationSystems based analysis of human embryos and gene networks involved in cell lineage allocation
Smith, H., Stevens, A., Minogue, B. M., Sneddon, S., Shaw, L., Wood, L., Adeniyi, T., Xiao, H., Lió, P., Kimber, S. J., et al. (2019) · BMC Genomics · doi:10.1186/s12864-019-5558-8 · Cited by 20 · see citing works
Self-citationInsights into pubertal development: a narrative review on the role of epigenetics
Shulhai, A.-M., Munerati, A., Menzella, M., Palanza, P., Esposito, S., & Street, M. E. (2024) · Journal of Endocrinological Investigation · doi:10.1007/s40618-024-02513-0 · Cited by 18 · see citing works
Cooper, D. M., & Radom‐Aizik, S. (2019) · Pediatric Research · doi:10.1038/s41390-019-0581-7 · Cited by 17 · see citing works
Moreno, J. P., Crowley, S. J., Alfano, C. A., & Thompson, D. I. (2019) · Obesity Reviews · doi:10.1111/obr.12973 · Cited by 17 · see citing works
No population left behind: Improving paediatric drug safety using informatics and systems biology
Giangreco, N., Elias, J. E., & Tatonetti, N. P. (2020) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.14705 · Cited by 17 · see citing works
GH deficiency status combined with GH receptor polymorphism affects response to GH in children
Valsesia, A., Chatelain, P., Stevens, A., Peterkova, V. A., Belgorosky, A., Maghnie, M., Antoniazzi, F., Koledova, E. B., Wojcik, J., Farmer, P. J., et al. (2015) · European Journal of Endocrinology · doi:10.1530/eje-15-0474 · Cited by 16 · see citing works
Self-citationEvolutionary conserved networks of human height identify multiple Mendelian causes of short stature
Hauer, N. N., Popp, B., Taher, L., Vogl, C., Dhandapany, P. S., Büttner, C., Uebe, S., Sticht, H., Ferrazzi, F., Ekici, A. B., et al. (2019) · European Journal of Human Genetics · doi:10.1038/s41431-019-0362-0 · Cited by 16 · see citing works
Giangreco, N. P., & Tatonetti, N. P. (2022) · Med · doi:10.1016/j.medj.2022.06.001 · Cited by 16 · see citing works
Stevens, A., Murray, P. G., Wojcik, J., Raelson, J., Koledova, E. B., Chatelain, P., Clayton, P., & _, _. (2016) · European Journal of Endocrinology · doi:10.1530/eje-16-0357 · Cited by 14 · see citing works
Self-citationStevens, A., Meyer, S., Hanson, D., Clayton, P., & Donn, R. P. (2014) · Arthritis Research & Therapy · doi:10.1186/ar4559 · Cited by 13 · see citing works
Self-citationGene expression signatures predict response to therapy with growth hormone
Stevens, A., Murray, P. G., Leonibus, C. D., Garner, T., Koledova, E. B., Ambler, G. R., Hou, J.-W., Kapelari, K., Salles, J., Binder, G., et al. (2021) · The Pharmacogenomics Journal · doi:10.1038/s41397-021-00237-5 · Cited by 12 · see citing works
Self-citationWarming during embryogenesis induces a lasting transcriptomic signature in fishes
Ripley, D. M., Garner, T., Hook, S. A., Veríssimo, A., Grunow, B., Moritz, T., Clayton, P., Shiels, H. A., & Stevens, A. (2023) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2023.165954 · Cited by 12 · see citing works
Self-citationPharmacogenetics: Applications to Pediatric Patients
de Beaumais, T. A., & Jacqz-Aigrain, É. (2018) · Advances in pharmacology · doi:10.1016/bs.apha.2018.04.006 · Cited by 12 · see citing works
Berghänel, A., Stevens, J. M. G., Hohmann, G., Deschner, T., & Behringer, V. (2023) · eLife · doi:10.7554/elife.86635 · Cited by 11 · see citing works
Chen, J., Xiao, W., Zhao, J., Heitkamp, M., Chen, D., Shan, R., Yang, Z., & Liu, Z. (2024) · Obesity Reviews · doi:10.1111/obr.13715 · Cited by 11 · see citing works
Peek, G. W., & Tollefsbol, T. O. (2015) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25462 · Cited by 11 · see citing works
Donn, R. P., Leonibus, C. D., Meyer, S., & Stevens, A. (2016) · Pediatric Rheumatology · doi:10.1186/s12969-016-0078-4 · Cited by 11 · see citing works
Self-citationElands, R. J. J., Simons, C. C. J. M., Riemenschneider, M., Isaacs, A. J., Schouten, L. J., Verhage, B. A. J., Steen, K. V., Godschalk, R., van den Brandt, P. A., Stoll, M., et al. (2017) · Scientific Reports · doi:10.1038/srep41034 · Cited by 11 · see citing works
Stevens, A., Perchard, R., Garner, T., Clayton, P., & Murray, P. G. (2021) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-021-09637-1 · Cited by 11 · see citing works
Self-citationPharmacogenomics Related to Growth Disorders
Stevens, A., Leonibus, C. D., Whatmore, A. J., Hanson, D., Murray, P. G., Chatelain, P., Westwood, M., & Clayton, P. (2013) · Hormone Research in Paediatrics · doi:10.1159/000355658 · Cited by 9 · see citing works
Self-citationA high-quality annotated transcriptome of swine peripheral blood
Liu, H., Smith, T. P. L., Nonneman, D., Dekkers, J. C. M., & Tuggle, C. K. (2017) · BMC Genomics · doi:10.1186/s12864-017-3863-7 · Cited by 9 · see citing works
Yang, Y., Tong, M., & de la Monte, S. M. (2024) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-240026 · Cited by 8 · see citing works
Nonlinear transcriptomic response to dietary fat intake in the small intestine of C57BL/6J mice
Nyima, T., Müller, M. M., Hooiveld, G. J. E. J., Morine, M. J., & Scotti, M. (2016) · BMC Genomics · doi:10.1186/s12864-016-2424-9 · Cited by 8 · see citing works
Bridging the Gaps: The Promise of Omics Studies in Pediatric Exercise Research
Radom‐Aizik, S., & Cooper, D. M. (2016) · Pediatric Exercise Science · doi:10.1123/pes.2015-0270 · Cited by 7 · see citing works
Pharmacogenetics and application in pediatrics
Neyro, V., Jacqz-Aigrain, É., & de Beaumais, T. A. (2018) · Therapies · doi:10.1016/j.therap.2017.11.010 · Cited by 7 · see citing works
Zhao, J., Bian, J., Zhao, Y., Li, Y., Liu, B., Hao, X., He, S., & Huang, L. (2023) · Pediatric Drugs · doi:10.1007/s40272-023-00560-3 · Cited by 6 · see citing works
Stevens, A., Hanson, D., Leonibus, C. D., Whatmore, A. J., Donn, R. P., White, D. J., Liu, J., van den Heuvel‐Eibrink, M. M., Saha, V., Clayton, P., et al. (2014) · Blood Cancer Journal · doi:10.1038/bcj.2013.76 · Cited by 6 · see citing works
Self-citationHaan, S., Bahlawane, C., Wang, J., Nazarov, P. V., Muller, A., Eulenfeld, R., Haan, C., Rolvering, C., Vallar, L., Satagopam, V., et al. (2015) · JAK-STAT · doi:10.1080/21623996.2015.1062596 · Cited by 5 · see citing works
Glucocorticoid Hormones in Aging
Kharwanlang, B., & Sharma, R. (2017) · Healthy ageing and longevity · doi:10.1007/978-3-319-63001-4_3 · Cited by 5 · see citing works
Secular Trends in Physical Growth Among Peruvian Children and Adolescents Living at High Altitudes
Bustamante, A., Santos, C., Maia, J. A. R., Freitas, D. L., Garganta, R., Katzmarzyk, P. T., & Pereira, S. (2024) · American Journal of Human Biology · doi:10.1002/ajhb.24169 · Cited by 4 · see citing works
Giangreco, N., & Tatonetti, N. P. (2021) · BioData Mining · doi:10.1186/s13040-021-00264-9 · Cited by 4 · see citing works
Parsons, S., Stevens, A., Whatmore, A. J., Clayton, P., & Murray, P. G. (2022) · Journal of the Endocrine Society · doi:10.1210/jendso/bvac006 · Cited by 4 · see citing works
Self-citationThe underlying metabolism of hypoalbuminemia and its clinical effects
Soeters, P. B., & de Leeuw, P. W. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820205-0.00010-4 · Cited by 3 · see citing works
de Almeida, R. J., Hirata, A. H. D. L., Rocha, L. A. D. J., Motta, M. D. D. A., Varela, P., Martins, L. D. O., Pesquero, J. B., & Camacho, C. P. (2023) · Archives of Endocrinology and Metabolism · doi:10.20945/2359-3997000000625 · Cited by 3 · see citing works
Teo, S. M., Segurado, R., Douglass, A., McAuliffe, F. M., Murrin, C. M., Kelleher, C. C., & Phillips, C. M. (2025) · American Journal of Clinical Nutrition · doi:10.1016/j.ajcnut.2025.03.016 · Cited by 2 · see citing works
Bone Development in Children and Adolescents
Boyanov, M. (2016) · Springer eBooks · doi:10.1007/978-3-319-32122-6_6 · Cited by 2 · see citing works
Exercise and Lung Function in Child Health and Disease
Cooper, D. M., Bar‐Yoseph, R., Olin, J. T., & Radom‐Aizik, S. (2019) · Elsevier eBooks · doi:10.1016/b978-0-323-44887-1.00012-2 · Cited by 2 · see citing works
Rieder, M. J., & Elzagallaai, A. A. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2573-6_20 · Cited by 1 · see citing works
Lawler, D. F., Tangredi, B. P., Widga, C., Etnier, M. A., Martin, T. J., Schulz, K. S., & Kohn, L. A. P. (2025) · Acta Zoologica · doi:10.1111/azo.12542 · Cited by 1 · see citing works
Cassat, S. (2015) · KU ScholarWorks (The University of Kansas)
Donn, R. P., & Stevens, A. (2017) · Rheumatology · doi:10.1093/rheumatology/kex390.041
Self-citationHistory of Drug Reaction in Children Suffering from Cancer
Zafar, B., Ghaffar, M., & Salahuddin, H. (2020) · Springer eBooks · doi:10.1007/978-981-15-1067-0_15
Gibney, J., Banerjee, I., & Ho, K. K. Y. (2022) · doi:10.1093/med/9780198870197.003.0005
Tanty, D. K., Sahu, P. R., Behera, S., Mohapatra, R., Behera, P. M., & Sahu, S. K. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.08.26.505395
Adolescent length growth spurts in bonobos and other primates: Mind the scalePreprint
Berghänel, A., Stevens, J. M. G., Hohmann, G., Deschner, T., & Behringer, V. (2023) · eLife · doi:10.7554/elife.86635.1
Cooper, D. M., & Radom‐Aizik, S. (2023) · Oxford University Press eBooks · doi:10.1093/med/9780192843968.003.0014
Evans, B. L., Garner, T., Leonibus, C. D., Wright, L., Sharps, M. C., Wearing, O. H., Ripley, D. M., Shiels, H. A., Hurlstone, A. F. L., Clayton, P., et al. (2025) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-025-05784-9
Self-citation
- Authors
- Stevens, A., Hanson, D., Whatmore, A., Destenaves, B., Chatelain, P., & Clayton, P.
- Affiliations
- Manchester Academic Health Science Centre (GB)
- Merck Serono S.A. (Switzerland) (CH)
- Lyon 1 Université (FR)
- Corresponding author
- Stevens, Adam
- Venue
- BMC Genomics
- Published
- 2013
- Volume
- 14
- Issue
- 1
- Pages
- 547
- ISSN
- 1471-2164 (ISSN-L)
- PMC
- PMC3765282
- OpenAlex
- W1972338105
- Cited by
- 65
- References
- 87
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 9 · 2022: 6 · 2021: 4 · 2020: 3 · 2019: 6 · 2018: 5 · 2017: 5 · 2016: 8 · 2015: 6 · 2014: 4 · 2013: 3
- FWCI
- 5.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- BMC Genomics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- human growth, gene expression profiling, puberty, growth spurt, longitudinal bone growth, Notch signaling, vascular endothelial growth factor, TGF-beta, Wnt signaling, glucocorticoid receptor, lymphoid cells, child development, developmental gene expression, biomarkers, therapeutic target
- MeSH terms
- Adolescent, Adult, Age Factors, Animals, Carrier Proteins, Child, Child, Preschool, Biological Evolution, Gene Expression Regulation, Growth, Humans, Infant, Protein Binding, Receptors, Glucocorticoid, Signal Transduction, Cluster Analysis, Gene Expression Profiling, Protein Interaction Mapping, Gene Regulatory Networks, Genome-Wide Association Study, Young Adult, Host Specificity
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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