A Multi-Omic Analysis of Birthweight in Newborn Cord Blood

Background: Birthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited. Methods: To investigate the systems biology of birthweight, we integrated methylome, transcriptome, metabolome and a set of inflammatory proteins measured in cord blood samples from four birth-cohorts (n=489). We focused on two sets of 68 metabolites and 903 CpGs previously related to birthweight and investigated the correlation structures existing between these two sets and all the other variables from different groups of omic data via bipartite Pearson correlations. Findings: Results substantiated previously identified biomarkers related to birthweight in cord blood, mostly involved in the regulation of the immune system, and identified new multiple omic features. Three metabolic features [PC(34:2), plasmalogen PC(36:4)/PC(O-36:5), and a compound with m/z of 781.0545], two CpGs (on the DHCR24 and SC4MOL gene), and two proteins (periostin and CCL22), were identified as key signals related to birthweight. Due to importance of the epigenetic signals in cholesterol biosynthesis, we further studied the association of cholesterol levels in cord blood with birthweight in the ENVIRONAGE cohort (n=1,096), finding that the increase of birthweight an was associated with increment of high-density lipoprotein cholesterol. Interpretation: Our data suggested that cholesterol metabolism in cord blood is involved in the birthweight mechanism and that integration of different omic layers is a useful approach to generate new hypotheses about biological mechanisms. Funding Statement: This work is supported by the Bijzonder Onderzoeksfonds (BOF) Hasselt University through a PhD fellowship [to RA], the “EXPOsOMICS” grant [grant number 308610-FP7 European Commission to PV], and the “STOP” grant [grant number 774548-European Commission H2020 to PV]. The ENVIRONAGE birth-cohort is supported by the EU Program “Ideas” (ERC-2012-StG 310898) and the FWO (G082317N). Piccolipiu cohort has been approved and initially funded by the CCM grant 2010 and by the Italian Ministry of Health. Declaration of Interests: The authors declare that they have no conflict of interests. Ethics Approval Statement: Piccolipiu cohort has been approved and initially funded by the CCM grant 2010 and by the Italian Ministry of Health.