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

Abstract

BackgroundThe 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.ObjectiveTo gain novel biological and therapeutic insights from the integrated analysis of magnetic resonance imaging and genetic data, informed by prior knowledge.MethodsWe 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.ResultsLipid 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).ConclusionsThis 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.

Expression of cytosolic malic enzyme (ME1) is associated with disease progression in human oral squamous cell carcinoma

“…KRAS , however, is not mutated in HSC3 cells. Other regulators of ME1 expression include the canonical wnt signaling pathway in breast cancers, a high‐fat diet in the intestinal epithelium and hepatocytes, and PPAR/EGR4 . Although a high‐fat diet and PPAR‐EGR4 contribute to lipogenesis, upregulation of ME1 did not induce lipogenesis in HSC3 cells (data not shown).…”

“…Several observations suggest that ME1 is a relevant therapeutic target. First, ME1 plays a role in acquisition of EMT phenotype through the PPAR signaling pathway, which upregulates yes‐associated protein and tafazzin . Yes‐associated protein and tafazzin interacts with Snail/Slug to control stem cell function and expression of the mesenchymal phenotype .…”

Imaging structural and functional brain development in early childhood

“…This is the first study of its kind 162 and independent replication is crucial, especially for the IGFBP7 intronic SNP, which was imputed, has a low minor allele frequency, and was not present in the largest racial/ethnic group in the study. A separate study 165 also used genome-wide data and pathway- and network-based approaches to investigate whether common genetic variation influences white-matter microstructure in preterm infants. The results indicated a possible role for peroxisome proliferator-activated receptor (PPAR) signaling in white matter development in preterm infants ; however, this study might best be considered a proof-of-concept study, given its very small sample size.…”

Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain

“…To test our prediction of a link between WNT and preterm brain connectivity we performed an analysis where we jointly analysed connectivity data derived from MRI and genomics data from 290 preterm born infants. This approach has previously uncovered novel genetic variants associated with brain connectivity phenotype (Krishnan et al, 2016;Krishnan et al, 2017). The pre-term born infants included in this study are described in more detail in Supp Table 4 and the inclusion/exclusion criteria are outlined in the materials and methods.…”