Centre for the Developing Brain King's College London St Thomas' Hospital London SE1 7EH UK.
Department of Biomedical Engineering King's College London St Thomas' Hospital London SE1 7EH UK.
Brain Behav. 2016 Apr 2;6(7):e00434. doi: 10.1002/brb3.434. eCollection 2016 Jul.
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.
早产儿的后果是一个主要的公共卫生问题，随之而来的多系统发病，其发病机制尚不确定。常见的遗传变异可能介导对早产损伤的易感性，并为预测和改变风险提供机会。
从磁共振成像和遗传数据的综合分析中获得新的生物学和治疗学见解，并利用先验知识。
我们应用以前验证过的基于途径的统计方法和一种新的基于网络的方法，发现与结构脑损伤的影像学特征相关的常见遗传变异的来源。
在一个研究早产影响的模型中，脂质途径在途径稀疏降秩回归中排名很高，一旦考虑到早产的程度，PPAR（过氧化物酶体增殖物激活受体）信号是排名最高的途径。在 PPAR 途径中，Graph Guided Group Lasso 发现有五个基因与表型高度相关：水通道蛋白 7（AQP7）、苹果酸酶 1、NADP（+）依赖性、胞质（ME1）、围脂素 1（PLIN1）、溶质载体家族 27（脂肪酸转运蛋白），成员 1（SLC27A1）和乙酰辅酶 A 酰基转移酶 1（ACAA1）。其中四种基因（ACAA1、AQP7、ME1 和 SLC27A1）的表达受共同的转录因子早期生长反应 4（EGR-4）控制。
这表明脂质途径在影响早产儿白质发育方面起着重要作用，特别是个体间 PPAR 信号遗传变异的重要作用。
