Prenatal environmental exposures associated with sex differences in childhood obesity and neurodevelopment

Background Obesity and neurodevelopmental delay are complex traits that often co-occur and differ between boys and girls. Prenatal exposures are believed to influence children’s obesity, but it is unknown whether exposures of pregnant mothers can confer a different risk of obesity between sexes, and whether they can affect neurodevelopment. Methods We analyzed data from 1044 children from the HELIX project, comprising 93 exposures during pregnancy, and clinical, neuropsychological, and methylation data during childhood (5–11 years). Using exposome-wide interaction analyses, we identified prenatal exposures with the highest sexual dimorphism in obesity risk, which were used to create a multiexposure profile. We applied causal random forest to classify individuals into two environments: E1 and E0. E1 consists of a combination of exposure levels where girls have significantly less risk of obesity than boys, as compared to E0, which consists of the remaining combination of exposure levels. We investigated whether the association between sex and neurodevelopmental delay also differed between E0 and E1. We used methylation data to perform an epigenome-wide association study between the environments to see the effect of belonging to E1 or E0 at the molecular level. Results We observed that E1 was defined by the combination of low dairy consumption, non-smokers’ cotinine levels in blood, low facility richness, and the presence of green spaces during pregnancy (ORinteraction¿=¿0.070, P¿=¿2.59¿×¿10-5). E1 was also associated with a lower risk of neurodevelopmental delay in girls, based on neuropsychological tests of non-verbal intelligence (ORinteraction¿=¿0.42, P¿=¿0.047) and working memory (ORinteraction¿=¿0.31, P¿=¿0.02). In line with this, several neurodevelopmental functions were enriched in significant differentially methylated probes between E1 and E0. Conclusions The risk of obesity can be different for boys and girls in certain prenatal environments. We identified an environment combining four exposure levels that protect girls from obesity and neurodevelopment delay. The combination of single exposures into multiexposure profiles using causal inference can help determine populations at risk.Peer ReviewedPostprint (published version

The early-life exposome modulates the effect of polymorphic inversions on DNA methylation

Polymorphic genomic inversions are chromosomal variants with intrinsic variability that play important roles in evolution, environmental adaptation, and complex traits. We investigated the DNA methylation patterns of three common human inversions, at 8p23.1, 16p11.2, and 17q21.31 in 1,009 blood samples from children from the Human Early Life Exposome (HELIX) project and in 39 prenatal heart tissue samples. We found inversion-state specific methylation patterns within and nearby flanking each inversion region in both datasets. Additionally, numerous inversion-exposure interactions on methylation levels were identified from early-life exposome data comprising 64 exposures. For instance, children homozygous at inv-8p23.1 and higher meat intake were more susceptible to TDH hypermethylation (P¿=¿3.8¿×¿10-22); being the inversion, exposure, and gene known risk factors for adult obesity. Inv-8p23.1 associated hypermethylation of GATA4 was also detected across numerous exposures. Our data suggests that the pleiotropic influence of inversions during development and lifetime could be substantially mediated by allele-specific methylation patterns which can be modulated by the exposome.Peer ReviewedPostprint (published version

OMICmAge : an integrative multi-omics approach to quantify biological age with electronic medical records

Biological aging is a multifactorial process involving complex interactions of cellular and biochemical processes that is reflected in omic profiles. Using common clinical laboratory measures in ~30,000 individuals from the MGB-Biobank, we developed a robust, predictive biological aging phenotype, EMRAge, that balances clinical biomarkers with overall mortality risk and can be broadly recapitulated across EMRs. We then applied elastic-net regression to model EMRAge with DNA-methylation (DNAm) and multiple omics, generating DNAmEMRAge and OMICmAge, respectively. Both biomarkers demonstrated strong associations with chronic diseases and mortality that outperform current biomarkers across our discovery (MGB-ABC, n=3,451) and validation TruDiagnostic, n=12,666) cohorts. Through the use of epigenetic biomarker proxies, OMICmAge has the unique advantage of expanding the predictive search space to include epigenomic, proteomic, metabolomic, and clinical data while distilling this in a measure with DNAm alone, providing opportunities to identify clinically-relevant interconnections central to the aging process

The effect of genetic background and exposome on DNA methylation and its influence on human traits

DNA methylation is really important because it is altered due to genetic and environmental factors, and it is associated with common diseases. In this thesis, we identified new factors altering DNA methylation, including drug consumption (tobacco, alcohol, and marijuana), common polymorphic inversions, and the interaction between inversions and the exposome. For that, we used two study populations: children from the HELIX project and adults from the TruDiagnostic DNA Biobank. To better explain the association of DNA methylation with common diseases, we evaluated methylation changes as possible mediators. We found alcohol-related CpG sites significantly mediating the association between heavy drinking and hypertension risk. We also identified an environment defined by multiple pregnant exposures detectable through a DNA methylation profile where girls are more protected against obesity and neurodevelopment delay than boys. Our findings suggest new genetic and environmental factors modulating DNA methylation that should be considered for new targets in disease prevention.La metilació de l’ADN és important ja que pot alterar-se degut a factors genètics i ambientals i degut a què està associada amb malalties comuns. En aquesta tesi, hem identificat nous factors que alteren la metilació, incloent el consum de drogues (tabac, alcohol i marihuana), les inversions comunes polimòrfiques, i la interacció entre les inversions i l’exposoma. Per això, hem utilitzat dues poblacions: nens del projecte HELIX i adults del Biobanc de TruDiagnostic. Per entendre millor l’associació entre la metilació i el risc a malalties, hem avaluat els canvis en la metilació com possibles mediadors. Hem trobat llocs CpG mediant significativament l’associació entre el consum excessiu d’alcohol i el risc a hipertensió. També hem identificat un ambient definit per múltiples exposicions prenatals on les noies estan més protegides de patir obesitat i retràs en el neurodesenvolupament que els nois. Els nostres resultats suggereixen nous factors moduladors de la metilació que haurien de considerar-se com noves dianes en la prevenció de malalties.Programa de Doctorat en Biomedicin

¿Qué piensan tus células de que fumes marihuana?

Guanyadora del 2n premi Rin4' 2022Doctorat en Biomedicina, Curs 2021-202

Impact of tobacco, alcohol, and marijuana on genome-wide DNA methylation and its relationship with hypertension

Tobacco, alcohol, and marijuana consumption is an important public health problem because of their high use worldwide and their association with the risk of mortality and many health conditions, such as hypertension, which is the commonest risk factor for death throughout the world. A likely pathway of action of substance consumption leading to persistent hypertension is DNA methylation. Here, we evaluated the effects of tobacco, alcohol, and marijuana on DNA methylation in the same cohort (N = 3,424). Three epigenome-wide association studies (EWAS) were assessed in whole blood using the InfiniumHumanMethylationEPIC BeadChip. We also evaluated the mediation of the top CpG sites in the association between substance consumption and hypertension. Our analyses showed 2,569 CpG sites differentially methylated by alcohol drinking and 528 by tobacco smoking. We did not find significant associations with marijuana consumption after correcting for multiple comparisons. We found 61 genes overlapping between alcohol and tobacco that were enriched in biological processes involved in the nervous and cardiovascular systems. In the mediation analysis, we found 66 CpG sites that significantly mediated the effect of alcohol consumption on hypertension. The top alcohol-related CpG site (cg06690548, P-value = 5.9·10 −83) mapped to SLC7A11 strongly mediated 70.5% of the effect of alcohol consumption on hypertension (P-value = 0.006). Our findings suggest that DNA methylation should be considered for new targets in hypertension prevention and management, particularly concerning alcohol consumption. Our data also encourage further research into the use of methylation in blood to study the neurological and cardiovascular effects of substance consumption

Impact of tobacco, alcohol, and marijuana on genome-wide DNA methylation and its relationship with hypertension

Tobacco, alcohol, and marijuana consumption is an important public health problem because of their high use worldwide and their association with the risk of mortality and many health conditions, such as hypertension, which is the commonest risk factor for death throughout the world. A likely pathway of action of substance consumption leading to persistent hypertension is DNA methylation. Here, we evaluated the effects of tobacco, alcohol, and marijuana on DNA methylation in the same cohort (N = 3,424). Three epigenome-wide association studies (EWAS) were assessed in whole blood using the InfiniumHumanMethylationEPIC BeadChip. We also evaluated the mediation of the top CpG sites in the association between substance consumption and hypertension. Our analyses showed 2,569 CpG sites differentially methylated by alcohol drinking and 528 by tobacco smoking. We did not find significant associations with marijuana consumption after correcting for multiple comparisons. We found 61 genes overlapping between alcohol and tobacco that were enriched in biological processes involved in the nervous and cardiovascular systems. In the mediation analysis, we found 66 CpG sites that significantly mediated the effect of alcohol consumption on hypertension. The top alcohol-related CpG site (cg06690548, P-value = 5.9·10−83) mapped to SLC7A11 strongly mediated 70.5% of the effect of alcohol consumption on hypertension (P-value = 0.006). Our findings suggest that DNA methylation should be considered for new targets in hypertension prevention and management, particularly concerning alcohol consumption. Our data also encourage further research into the use of methylation in blood to study the neurological and cardiovascular effects of substance consumption

Prenatal environmental exposures associated with sex differences in childhood obesity and neurodevelopment

Background: Obesity and neurodevelopmental delay are complex traits that often co-occur and differ between boys and girls. Prenatal exposures are believed to influence children's obesity, but it is unknown whether exposures of pregnant mothers can confer a different risk of obesity between sexes, and whether they can affect neurodevelopment. Methods: We analyzed data from 1044 children from the HELIX project, comprising 93 exposures during pregnancy, and clinical, neuropsychological, and methylation data during childhood (5-11 years). Using exposome-wide interaction analyses, we identified prenatal exposures with the highest sexual dimorphism in obesity risk, which were used to create a multiexposure profile. We applied causal random forest to classify individuals into two environments: E1 and E0. E1 consists of a combination of exposure levels where girls have significantly less risk of obesity than boys, as compared to E0, which consists of the remaining combination of exposure levels. We investigated whether the association between sex and neurodevelopmental delay also differed between E0 and E1. We used methylation data to perform an epigenome-wide association study between the environments to see the effect of belonging to E1 or E0 at the molecular level. Results: We observed that E1 was defined by the combination of low dairy consumption, non-smokers' cotinine levels in blood, low facility richness, and the presence of green spaces during pregnancy (ORinteraction = 0.070, P = 2.59 × 10-5). E1 was also associated with a lower risk of neurodevelopmental delay in girls, based on neuropsychological tests of non-verbal intelligence (ORinteraction = 0.42, P = 0.047) and working memory (ORinteraction = 0.31, P = 0.02). In line with this, several neurodevelopmental functions were enriched in significant differentially methylated probes between E1 and E0. Conclusions: The risk of obesity can be different for boys and girls in certain prenatal environments. We identified an environment combining four exposure levels that protect girls from obesity and neurodevelopment delay. The combination of single exposures into multiexposure profiles using causal inference can help determine populations at risk.The study has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no 308333 (HELIX project); and the H2020-EU.3.1.2.—Preventing Disease Programme under grant agreement no 874583 (ATHLETE project). BiB received core infrastructure funding from the Wellcome Trust (WT101597MA) and a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1). INMA-SAB data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6–04-2014_31V-66). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX), and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011–2014; “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–15). This research has received funding from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023 (CEX2018-000,806-S) program, and support from the Generalitat de Catalunya through the CERCA Program. NC and JU are supported by Spanish regional program PERIS (Ref.: SLT017/20/000061 and SLT017/20/000119, respectively), granted by Departament de Salut de la Generalitat de Catalunya. TruDiagnostics also provided funding for data analysis

The early-life exposome modulates the effect of polymorphic inversions on DNA methylation

Polymorphic genomic inversions are chromosomal variants with intrinsic variability that play important roles in evolution, environmental adaptation, and complex traits. We investigated the DNA methylation patterns of three common human inversions, at 8p23.1, 16p11.2, and 17q21.31 in 1,009 blood samples from children from the Human Early Life Exposome (HELIX) project and in 39 prenatal heart tissue samples. We found inversion-state specific methylation patterns within and nearby flanking each inversion region in both datasets. Additionally, numerous inversion-exposure interactions on methylation levels were identified from early-life exposome data comprising 64 exposures. For instance, children homozygous at inv-8p23.1 and higher meat intake were more susceptible to TDH hypermethylation (P = 3.8 × 10-22); being the inversion, exposure, and gene known risk factors for adult obesity. Inv-8p23.1 associated hypermethylation of GATA4 was also detected across numerous exposures. Our data suggests that the pleiotropic influence of inversions during development and lifetime could be substantially mediated by allele-specific methylation patterns which can be modulated by the exposome.The study has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no 308333 (HELIX project), and the H2020-EU.3.1.2.—Preventing Disease Programme under grant agreement no 874583 (ATHLETE project). The HELIX genotyping was supported by the projects PI17/01225 and PI17/01935, funded by the Instituto de Salud Carlos III and cofunded by European Union (ERDF, “A way to make Europe”) and the Centro Nacional de Genotipado-CEGEN (PRB2-ISCIII). BiB received core infrastructure funding from the Wellcome Trust (WT101597MA) and a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1). INMA-SAB data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU FP7-HEALTH-2012 Proposal No 308333 HELIX). This research has received funding from the Spanish Ministry of Education, Innovation and Universities, the National Agency for Research and the Fund for Regional Development (RTI2018-100789-B-I00), MaratóTV3 (2015–3230), the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019-2023 (CEX2018-000806-S) and Maria de Maeztu (MDM-2014-0370)” Programs, and support from the Generalitat de Catalunya through the CERCA and Consolidated Research Group (2017SGR01974) Programs. NC and JU are supported by Spanish regional program PERIS (Ref.: SLT017/20/000061 and SLT017/20/000119, respectively), granted by Departament de Salut de la Generalitat de Cataluny

Prenatal environmental exposures associated with sex differences in childhood obesity and neurodevelopment

Obesity and neurodevelopmental delay are complex traits that often co-occur and differ between boys and girls. Prenatal exposures are believed to influence children's obesity, but it is unknown whether exposures of pregnant mothers can confer a different risk of obesity between sexes, and whether they can affect neurodevelopment. We analyzed data from 1044 children from the HELIX project, comprising 93 exposures during pregnancy, and clinical, neuropsychological, and methylation data during childhood (5-11 years). Using exposome-wide interaction analyses, we identified prenatal exposures with the highest sexual dimorphism in obesity risk, which were used to create a multiexposure profile. We applied causal random forest to classify individuals into two environments: E1 and E0. E1 consists of a combination of exposure levels where girls have significantly less risk of obesity than boys, as compared to E0, which consists of the remaining combination of exposure levels. We investigated whether the association between sex and neurodevelopmental delay also differed between E0 and E1. We used methylation data to perform an epigenome-wide association study between the environments to see the effect of belonging to E1 or E0 at the molecular level. We observed that E1 was defined by the combination of low dairy consumption, non-smokers' cotinine levels in blood, low facility richness, and the presence of green spaces during pregnancy (OR = 0.070, P = 2.59 × 10 −5). E1 was also associated with a lower risk of neurodevelopmental delay in girls, based on neuropsychological tests of non-verbal intelligence (OR = 0.42, P = 0.047) and working memory (OR = 0.31, P = 0.02). In line with this, several neurodevelopmental functions were enriched in significant differentially methylated probes between E1 and E0. The risk of obesity can be different for boys and girls in certain prenatal environments. We identified an environment combining four exposure levels that protect girls from obesity and neurodevelopment delay. The combination of single exposures into multiexposure profiles using causal inference can help determine populations at risk