Possible relationship between common genetic variation and white matter development in a pilot study of preterm infants.
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.



To gain novel biological and therapeutic insights from the integrated analysis of magnetic resonance imaging and genetic data, informed by prior knowledge.



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.



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 (AQP7), malic enzyme 1, NADP(+)-dependent, cytosolic (ME1), perilipin 1 (PLIN1), solute carrier family 27 (fatty acid transporter), member 1 (SLC27A1), and acetyl-CoA acyltransferase 1 (ACAA1). Expression of four of these (ACAA1, AQP7, ME1, and SLC27A1) is controlled by a common transcription factor, early growth response 4 (EGR-4).



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.
Centre for the Developing Brain King's College London St Thomas' Hospital London SE1 7EH UK.
Michelle L
ML
Krishnan
Department of Biomedical Engineering King's College London St Thomas' Hospital London SE1 7EH UK.
Zi
Z
Wang
Department of Population Health London School of Hygiene and Tropical Medicine London WC1E 7HT UK.
Matt
M
Silver
MRC Centre for Reproductive Health University of Edinburgh Edinburgh EH16 4TJ UK.
James P
JP
Boardman
Centre for the Developing Brain King's College London St Thomas' Hospital London SE1 7EH UK.
Gareth
G
Ball
Centre for the Developing Brain King's College London St Thomas' Hospital London SE1 7EH UK.
Serena J
SJ
Counsell
School of Public Health Faculty of Medicine Imperial College London Norfolk Place London W2 1PG UK.
Andrew J
AJ
Walley
Department of Biomedical Engineering King's College London St Thomas' Hospital London SE1 7EH UK.
Giovanni
G
Montana
Centre for the Developing Brain King's College London St Thomas' Hospital London SE1 7EH UK.
Anthony David
AD
Edwards
D001930:Brain Injuries / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D038524:Diffusion Magnetic Resonance Imaging; D014644:Genetic Variation; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D050356:Lipid Metabolism / Q000235:genetics; D010641:Phenotype; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D066127:White Matter / Q000000981:diagnostic imaging / Q000254:growth & development / Q000473:pathology / Q000502:physiology*
Brain development; genomics; lipids; magnetic resonance imaging; metabolic pathways; multivariate analysis; neonatal; single‐nucleotide polymorphism