TY - JOUR
T1 - Epigenome-wide analysis of maternal exposure to green space during gestation and cord blood DNA methylation in the ENVIRONAGE cohort
AU - Alfano, Rossella
AU - Bijnens, Esmée
AU - Langie, Sabine A.S.
AU - Nawrot, Tim S.
AU - Reimann, Brigitte
AU - Vanbrabant, Kenneth
AU - Wang, Congrong
AU - Plusquin, Michelle
N1 - Funding Information:
This work is supported by the Bijzonder Onderzoeksfonds Hasselt University through PhD fellowships [to RA, BR, CW], the Flemish Scientific Fund ( G059219N ) [to KV] and the Marguerite-Marie Delacroix foundation [to EMB] and the province of Limburg. The ENVIRONAGE cohort is supported by the EU Research Council “project ENVIRONAGE” ( ERC-2012-StG 310,89 0), the Flemish Scientific Fund ( G073315N/G048420N/G026222 N) and the Methusalem funding. The generation of DNA methylation data have been additionally supported from the EXPOsOMICS project and the Research Foundation – Flanders ( FWO ) grant 1523817N [to SL].
Publisher Copyright:
© 2022 The Authors
PY - 2023/1/1
Y1 - 2023/1/1
N2 - Background: DNA methylation programming is sensitive to prenatal life environmental influences, but the impact of maternal exposure to green space on newborns DNA methylation has not been studied yet. Methods: We conducted a meta-epigenome-wide association study (EWAS) of maternal exposure to green space during gestation with cord blood DNA methylation in two subsets of the ENVIRONAGE cohort (N = 538). Cord blood DNA methylation was measured by Illumina HumanMethylation 450K in one subset (N = 189) and EPICarray in another (N = 349). High (vegetation height>3 m (m)), low (vegetation height<3 m) and total (including both) high-resolution green space exposures during pregnancy were estimated within 100 m and 1000 m distance around maternal residence. In each subset, we sought cytosine-phosphate-guanine (CpG) sites via linear mixed models adjusted on newborns' sex, ethnicity, gestational age, season at delivery, sampling day, maternal parity, age, smoking, education, and estimated blood cell proportions. EWASs results were meta-analysed via fixed-effects meta-analyses. Differentially methylated regions (DMRs) were identified via ENmix-combp and DMRcate algorithms. Sensitivity analyses were additionally adjusted on PM2.5, distance to major roads, urbanicity and neighborhood income. In the 450K subset, cord blood expression of differentially methylated genes was measured by Agilent microarrays and associated with green space. Results: 147 DMRs were identified, 85 of which were still significant upon adjustment for PM2.5, distance to major roads, urbanicity and neighborhood income, including HLA-DRB5, RPTOR, KCNQ1DN, A1BG-AS1, HTR2A, ZNF274, COL11A1 and PRSS36 DMRs. One CpG reached genome-wide significance, while 54 CpGs were suggestive significant (p-values<1e-05). Among them, a CpG, hypermethylated with 100 m buffer total green space, was annotated to PAQR9, whose expression decreased with 1000 m buffer low green space (p-value = 1.45e-05). Conclusions: Our results demonstrate that maternal exposure to green space during pregnancy is associated with cord blood DNA methylation, mainly at loci organized in regions, in genes playing important roles in neurological development (e.g., HTR2A).
AB - Background: DNA methylation programming is sensitive to prenatal life environmental influences, but the impact of maternal exposure to green space on newborns DNA methylation has not been studied yet. Methods: We conducted a meta-epigenome-wide association study (EWAS) of maternal exposure to green space during gestation with cord blood DNA methylation in two subsets of the ENVIRONAGE cohort (N = 538). Cord blood DNA methylation was measured by Illumina HumanMethylation 450K in one subset (N = 189) and EPICarray in another (N = 349). High (vegetation height>3 m (m)), low (vegetation height<3 m) and total (including both) high-resolution green space exposures during pregnancy were estimated within 100 m and 1000 m distance around maternal residence. In each subset, we sought cytosine-phosphate-guanine (CpG) sites via linear mixed models adjusted on newborns' sex, ethnicity, gestational age, season at delivery, sampling day, maternal parity, age, smoking, education, and estimated blood cell proportions. EWASs results were meta-analysed via fixed-effects meta-analyses. Differentially methylated regions (DMRs) were identified via ENmix-combp and DMRcate algorithms. Sensitivity analyses were additionally adjusted on PM2.5, distance to major roads, urbanicity and neighborhood income. In the 450K subset, cord blood expression of differentially methylated genes was measured by Agilent microarrays and associated with green space. Results: 147 DMRs were identified, 85 of which were still significant upon adjustment for PM2.5, distance to major roads, urbanicity and neighborhood income, including HLA-DRB5, RPTOR, KCNQ1DN, A1BG-AS1, HTR2A, ZNF274, COL11A1 and PRSS36 DMRs. One CpG reached genome-wide significance, while 54 CpGs were suggestive significant (p-values<1e-05). Among them, a CpG, hypermethylated with 100 m buffer total green space, was annotated to PAQR9, whose expression decreased with 1000 m buffer low green space (p-value = 1.45e-05). Conclusions: Our results demonstrate that maternal exposure to green space during pregnancy is associated with cord blood DNA methylation, mainly at loci organized in regions, in genes playing important roles in neurological development (e.g., HTR2A).
KW - Differentially methylated regions
KW - DNA methylation
KW - Epigenome-wide
KW - Epigenomics
KW - Gene expression
KW - Maternal green space
UR - http://www.scopus.com/inward/record.url?scp=85142173532&partnerID=8YFLogxK
U2 - 10.1016/j.envres.2022.114828
DO - 10.1016/j.envres.2022.114828
M3 - Article
AN - SCOPUS:85142173532
SN - 0013-9351
VL - 216
SP - 1
EP - 10
JO - Environmental Research
JF - Environmental Research
IS - Part 4
M1 - 114828
ER -