Possible relationship between common genetic variation and white matter development in a pilot study of preterm infants
Open accessAbstract
Background: The consequences of preterm birth are a major public health concern with high rates of ensuing multisystem morbidity, and uncertain biological mechanisms. Common genetic variation may mediate vulnerability to the insult of prematurity and provide opportunities to predict and modify risk. Objective: To gain novel biological and therapeutic insights from the integrated analysis of magnetic resonance imaging and genetic data, informed by prior knowledge. Methods: We apply our previously validated pathway‐based statistical method and a novel network‐based method to discover sources of common genetic variation associated with imaging features indicative of structural brain damage. Results: Lipid pathways were highly ranked by Pathways Sparse Reduced Rank Regression in a model examining the effect of prematurity, and PPAR (peroxisome proliferator‐activated receptor) signaling was the highest ranked pathway once degree of prematurity was accounted for. Within the PPAR pathway, five genes were found by Graph Guided Group Lasso to be highly associated with the phenotype: aquaporin 7 (AQP 7), malic enzyme 1, NADP(+)‐dependent, cytosolic (ME 1), perilipin 1 (PLIN 1), solute carrier family 27 (fatty acid transporter), member 1 (SLC 27A1), and acetyl‐CoA acyltransferase 1 (ACAA 1). Expression of four of these (ACAA 1, AQP 7, ME 1, and SLC 27A1) is controlled by a common transcription factor, early growth response 4 (EGR‐4). Conclusions: This suggests an important role for lipid pathways in influencing development of white matter in preterm infants, and in particular a significant role for interindividual genetic variation in PPAR signaling.
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A separate study indicated a possible role for PPAR signaling in white matter development in preterm infants.
“The results indicated a possible role for peroxisome proliferator-activated receptor (PPAR) signaling in white matter development in preterm infants”
From Imaging structural and functional brain development in early childhood (2018) · cites this paper as [165]
That PPAR study is best considered a proof-of-concept study because of its very small sample size.
“this study might best be considered a proof-of-concept study, given its very small sample size.”
From Imaging structural and functional brain development in early childhood (2018) · cites this paper as [165]
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Development of cortical anatomical properties from early childhood to early adulthood
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Role of PPAR γ in the Differentiation and Function of Neurons
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Cortical Gray and Adjacent White Matter Demonstrate Synchronous Maturation in Very Preterm Infants
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Development of the optic radiations and visual function after premature birth
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Self-citationFatty acid binding proteins and the nervous system: Their impact on mental conditions
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Pregnancy Complications and the Risk of Metabolic Syndrome for the Offspring
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Genomic architecture of human neuroanatomical diversity
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White Matter Heritability Using Diffusion Tensor Imaging in Neonatal Brains
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Common Genetic Variants and Risk of Brain Injury After Preterm Birth
Boardman, J. P., Walley, A. J., Ball, G., Takousis, P., Krishnan, M. L., Hughes-Carre, L., Aljabar, P., Serag, A., King, C., Merchant, N. M., et al. (2014) · PEDIATRICS · doi:10.1542/peds.2013-3011 · Cited by 50 · see citing works
Self-citationInvestigating brain connectivity heritability in a twin study using diffusion imaging data
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Prematurity and programming of cardiovascular disease risk: a future challenge for public health?
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Silver, M. J., Chen, P., Li, R.-Y., Cheng, C.-Y., Wong, T., Tai, E., Teo, Y. Y., & Montana, G. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003939 · Cited by 44 · see citing works
Self-citationSilver, M. J., Montana, G., & Initiative, A. D. N. (2012) · Statistical Applications in Genetics and Molecular Biology · doi:10.2202/1544-6115.1755 · Cited by 43 · see citing works
Self-citationCurrent advances in systems and integrative biology
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Immunohistochemical expression of peroxisomal enzymes in developing human brain
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Current trends and future challenges in neonatal parenteral nutrition
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Guitart, M., Osorio-Conles, Ó., Pentinat, T., Cebrià, J., García‐Villoria, J., Sala, D., Sebastián, D., Zorzano, A., Ribes, A., Jiménez‐Chillarón, J. C., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098109 · Cited by 32 · see citing works
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Systems approach to the study of brain damage in the very preterm newborn
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Discovery and optimization of novel fatty acid transport protein 1 (FATP1) inhibitors
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The Graph-Guided Group Lasso for Genome-Wide Association Studies
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Imaging structural and functional brain development in early childhood
Gilmore, J. H., Knickmeyer, R. C., & Gao, W. (2018) · Nature Reviews Neuroscience · doi:10.1038/nrn.2018.1 · Cited by 1,013 · see citing works
An extra-uterine system to physiologically support the extreme premature lamb
Partridge, E. A., Davey, M. G., Hornick, M. A., McGovern, P. E., Mejaddam, A. Y., Vrecenak, J. D., Burgos, C. M., Olive, A. M., Caskey, R. C., Weiland, T. R., et al. (2017) · Nature Communications · doi:10.1038/ncomms15112 · Cited by 430 · see citing works
The emergence of functional architecture during early brain development
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Self-citationSteenwinckel, J. V., Schang, A., Krishnan, M. L., Degos, V., Delahaye‐Duriez, A., Bokobza, C., Csaba, Z., Verdonk, F., Montané, A., Sigaut, S., et al. (2019) · Brain · doi:10.1093/brain/awz319 · Cited by 150 · see citing works
Self-citationEarly breast milk exposure modifies brain connectivity in preterm infants
Blesa, M., Sullivan, G., Anblagan, D., Telford, E. J., Quigley, A. J., Sparrow, S. A., Serag, A., Semple, S. I. K., Bastin, M. E., & Boardman, J. P. (2018) · NeuroImage · doi:10.1016/j.neuroimage.2018.09.045 · Cited by 120 · see citing works
Self-citationKrishnan, M. L., Van Steenwinckel, J., Schang, A.-L., Yan, J., Arnadottir, J., Le Charpentier, T., Csaba, Z., Dournaud, P., Cipriani, S., Auvynet, C., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00422-w · Cited by 105 · see citing works
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A review on neuroimaging studies of genetic and environmental influences on early brain development
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Self-citationNakashima, C., Yamamoto, K., Fujiwara‐Tani, R., Luo, Y., Matsushima, S., Fujii, K., Ohmori, H., Sasahira, T., Sasaki, T., Kitadai, Y., et al. (2018) · Cancer Science · doi:10.1111/cas.13594 · Cited by 51 · see citing works
Fitzgerald, E., Boardman, J. P., & Drake, A. J. (2018) · Current Genomics · doi:10.2174/1389202919666171229144807 · Cited by 44 · see citing works
Self-citationGenetic Influences on the Developing Young Brain and Risk for Neuropsychiatric Disorders
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Self-citationCombined Transcriptomics, Proteomics and Bioinformatics Identify Drug Targets in Spinal Cord Injury
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Self-citationNeuroprotection of the preterm brain
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Multi-Channel 4D Parametrized Atlas of Macro- and Microstructural Neonatal Brain Development
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Self-citationSignificance of Malic Enzyme 1 in Cancer: A Review
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Self-citationThe neonatal brain : early connectome development and childhood cognition
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PPAR Gamma Receptor: A Novel Target to Improve Morbidity in Preterm Babies
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Self-citationNeurodevelopmental impact of perinatal inflammation : targets for neuroprotection?
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- Authors
- Krishnan, M. L., Wang, Z., Silver, M., Boardman, J. P., Ball, G., Counsell, S. J., Walley, A. J., Montana, G., & Edwards, A. D.
- Affiliations
- St Thomas' Hospital (GB)
- London School of Hygiene & Tropical Medicine (GB)
- MRC Centre for Reproductive Health (GB)
- Imperial College London (GB)
- Corresponding author
- Krishnan, Michelle L.
- ORCID
- Venue
- Brain and Behavior
- Publisher
- Wiley
- Published
- 2016-04-02
- Volume
- 6
- Issue
- 7
- Pages
- e00434-e00434
- ISSN
- 2157-9032 (ISSN-L)
- 2162-3279
- PMC
- PMC4821839
- OpenAlex
- W2328783496
- Cited by
- 28
- References
- 118
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2021: 2 · 2020: 1 · 2019: 5 · 2018: 10 · 2017: 6
- FWCI
- 8.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Brain and Behavior (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, cc-by)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- National Institute on Handicapped Research
- Guy's and St Thomas' NHS Foundation Trust
- Medical Research Council
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Infant Development and Preterm Care
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- preterm birth, white matter development, common genetic variants, PPAR signaling, lipid pathways, structural brain damage, AQP7, ME1, PLIN1, SLC27A1, gene expression, network-based methods, preterm infants
- MeSH terms
- Brain Injuries, Humans, Infant, Newborn, Infant, Premature, Phenotype, Pilot Projects, Genetic Variation, Polymorphism, Single Nucleotide, Diffusion Magnetic Resonance Imaging, Lipid Metabolism, White Matter
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