Life-course publications map

Publications from the LongITools project will be mapped against the life-course below. The coloured bars on the timeline show the ages of the people studied. The categories are either exposures, molecular responses or outcomes of the study.

Publications Map © Beta Technology Ltd 2020

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LongITools: Dynamic longitudinal exposome trajectories in cardiovascular and metabolic noncommunicable diseases

06/01/2022 - Justiina Ronkainen, Sylvain Sebert et al on behalf of the LongITools Project Group - University of Oulu, Erasmus MC, Imperial College London, Beta Technology, University of Eastern Finland, Chalmers University of Technology, University Medical Center Groningen, National Institute of Medical Research, University College London, Utrecht University, University of Surrey, Amsterdam University Medical Centers, location AMC, University of Oslo, University of Bristol, University of Barcelona, Ab.Acus, Cynexo, Tor Vergata University of Rome

This consortium profile paper introduces (1) LongITools’ scientific concepts that are primarily based on longitudinal modeling; (2) the metadata for the project; (3) the expected impact of the project; and finally (4) the strengths and challenges of this endeavor.

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Maternal plasma fatty acid patterns in mid-pregnancy and offspring epigenetic gestational age at birth

17/05/2022 - Giulietta S. Monasso et al. Epigenetics. LongITools authors: Janine Felix - Erasmus MC
Cohort(s): Generation R

Levels of fatty acids in maternal blood during pregnancy are associated with child health. Epigenetic gestational age acceleration, referring to a discrepancy between gestational age at birth and gestational age based on DNA methylation, may underlie these associations. The researchers found some evidence that a maternal plasma fatty acid pattern characterized by higher concentrations of n-3 polyunsaturated fatty acids may be associated with accelerated epigenetic gestational ageing. These findings depended on the method used and the accuracy of pregnancy dating and therefore need confirmation.

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Maternal dietary glycemic index and glycemic load in pregnancy and offspring cord blood DNA methylation

16/06/2022 - Leanne K. Küpers et al. Diabetes Care. LongITools authors: Romy Gaillard, Vincent Jaddoe and Janine Felix - Erasmus MC

Suboptimal nutrition in pregnancy is associated with worse offspring cardiometabolic health. DNA methylation may be an underlying mechanism. Researchers examined whether maternal dietary glycemic index and load are associated with cord blood DNA methylation in 2003 mother-child pairs from three cohorts. They observed multiple associations of maternal glycemic index and load during pregnancy with cord blood DNA methylation, mostly in mothers with overweight/obesity; some of these CpGs were associated with gene expression. Additional studies are required to further explore functionality, uncover causality, and study pathways to offspring health.

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Associations of circulating folate, vitamin B12 and homocysteine concentrations in early pregnancy and cord blood with epigenetic gestational age: the Generation R Study

29/04/2021 - Monasso G.S. et al. Clinical Epigenetics. LongITools authors: Vincent Jaddoe and Janine Felix - Erasmus MC
Cohort(s): Generation R

Concentrations of folate, vitamin B12 and homocysteine during pregnancy are associated with childhood health outcomes. In a population-based study of 1,346 mothers and newborns, we found some evidence to support associations of maternal plasma homocysteine concentrations with positive epigenetic gestational age acceleration, suggesting faster epigenetic than clinical gestational ageing. Cord serum vitamin B12 concentrations may be associated with negative gestational age acceleration, indicating slower epigenetic than clinical gestational ageing.

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Paternal body mass index and offspring DNA methylation: findings from the PACE consortium

29/01/2021 - Gemma C Sharp et al. International Journal of Epidemiology. LongITools authors: Vincent Jaddoe, Johanna Lepeule and Janine Felix - Erasmus MC, National Institute of Medical Research

Overweight and obesity in fathers around the time of conception is related to offspring health. Changes in DNA methylation may be an underlying biological mechanism. In a large study including data from almost 5000 newborns and almost 2000 children, we did not find evidence to support this.

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Maternal Mediterranean diet in pregnancy and newborn DNA methylation: a meta-analysis in the PACE Consortium

02/03/2022 - Leanne K. Küpersa et al. Epigenetics. LongITools authors: Vincent Jaddoe and Janine Felix - Erasmus MC
Cohort(s): ALSPAC, Generation R

Higher adherence to the Mediterranean diet during pregnancy is related to a lower risk of preterm birth and to better offspring cardiometabolic health. DNA methylation may be an underlying biological mechanism. The researchers evaluated whether maternal adherence to the Mediterranean diet was associated with offspring cord blood DNA methylation, in 2802 mother–child pairs from five cohorts. Higher adherence to the Mediterranean diet was associated with cord blood DNA methylation at cg23757341. This cytosine–phosphate–guanine (CpG) site maps to WNT5B, associated with adipogenesis and glycaemic phenotypes.

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Maternal iron status in early pregnancy and DNA methylation in offspring: an epigenome-wide meta-analysis

03/05/2022 - M. J. Taeubert et al. Clinical Epigenetics. LongITools authors: Janine Felix - Erasmus MC
Cohort(s): Generation R

Suboptimal, too low or too high, maternal iron status in pregnancy is associated with an increased risk of adverse birth and childhood health outcomes. DNA methylation has been suggested as a potential underlying mechanism. Maternal early-pregnancy serum ferritin concentrations, an indicator of iron status, were associated with lower cord blood DNA methylation levels at three CpGs and these associations partly persisted in older children. Further studies are needed to uncover the role of these CpGs in the underlying mechanisms of the associations of maternal iron status and offspring health outcomes.

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Vitamin B12, folate and homocysteine concentrations during pregnancy and early signs of atherosclerosis at school-age

01/09/2021 - Giulietta S. Monasso et al. Clinical Nutrition. LongITools authors: Janine Felix, Romy Gaillard and Vincent Jaddoe. - Erasmus MC
Cohort(s): Generation R

We examined if vitamin B12, folate and homocysteine concentrations are associated with vascular structure and function in 3,826 school-age children. We found that having a low vitamin B12 concentrations in early pregnancy was related with a higher thickness of the vascular wall and having a low folate concentration in early pregnancy was associated with a higher vascular stiffness. Similarly, higher homocysteine concentrations in cord blood were associated with higher vascular stiffness. This means that suboptimal concentrations of vitamin B12, folate and homocysteine seem to be related to worse cardiovascular risk factors at school-age. Whether these associations are causal and what the exact mechanisms are need to be further studied.

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Machine Learning-Based DNA Methylation Score for Fetal Exposure to Maternal Smoking: Development and Validation in Samples Collected from Adolescents and Adults

15/09/2020 - Rauschert S. et al. Environmental Health Perspectives. LongITools authors: Anni Heiskala, Ville Karhunen, Marjo-Riitta Järvelin and Sylvain Sebert - University of Oulu
Cohort(s): Northern Finland Birth Cohorts, Raine Study

Fetal exposure to maternal smoking during pregnancy is associated with the development of noncommunicable diseases in the offspring. Maternal smoking may induce such long-term effects through persistent changes in the DNA methylome, which therefore hold the potential to be used as a biomarker of this early life exposure. We have developed a DNA methylation score for exposure to maternal smoking during pregnancy. One possible application of the current score could be for model adjustment purposes or to assess its association with distal health outcomes where part of the effect can be attributed to maternal smoking. Furthermore, it may provide a biomarker for fetal exposure to maternal smoking.

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Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies

27/05/2022 - E.W. Tobi et al. Diabates Care. LongITools authors: Janine Felix, Barbara Huede, Vincent Jaddoe, Marjo-Riitta Järvelin and Sylvain Sebert. - University of Oulu, Erasmus MC, National Institute of Medical Research
Cohort(s): EDEN, Finnish Gestational Diabetes Study and Generation R

Analyses of oral glucose tolerance tests in pregnant women identified associations of an epigenetic marker (TXNIP) in the newborn of mothers with maternal hyperglycaemia, linked to a higher risk of type 2 diabetes. The study follows a decade of research aiming to understand how maternal glycaemic health and gestational diabetes could possibly transmit a risk of type 2 diabetes in the offspring through foetal programming.

Early exposure to social disadvantages and later life body mass index beyond genetic predisposition in three generations of Finnish birth cohorts

18/05/2020 - Lowry, E., Rautio, N., Wasenius, N. et al. BMC Public Health. LongITools Authors: Anni Heiskala, Leena Ala-Mursula, Jouko Miettunen, Marjo-Riitta Järvelin and Sylvain Sebert - University of Oulu
Cohort(s): Northern Finland Birth Cohorts, Helsinki Birth Cohort Study

High social disadvantage in early life appears to be associated with being with higher BMI in later life. Reducing exposure to social disadvantage during the life-course reduced the risk a and may be a potential pathway for obesity reduction.

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Epigenome-wide contributions to individual differences in childhood phenotypes: a GREML approach

19/04/2022 - Alexander Neumann et al. Clinical Epigenetics. LongITools authors: Vincent Jaddoe and Janine Felix - Erasmus MC
Cohort(s): ALSPAC, Generation R

The overall contribution of DNA methylation across the genome (R2Methylation) towards childhood phenotypes is unknown. The researchers estimated the variance explained by epigenome-wide cord blood methylation (R2Methylation) for five childhood phenotypes: gestational age, birth weight, and body mass index (BMI), IQ and ADHD symptoms at school age. The results suggest that cord blood methylation explains a moderate degree of variance in gestational age and birth weight. In contrast, a reliable estimate for school-age BMI, IQ and ADHD symptoms could not be obtained.

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Epigenetic age acceleration and cardiovascular outcomes in school-age children: The Generation R Study

16/11/2021 - Giulietta S Monasso et al. Clinical Epigenetics. LongITools authors: Vincent Jaddoe and Janine Felix - Erasmus MC
Cohort(s): Generation R

In this population-based study of 1,115 children from the Generation R Study, we examined if epigenetic age acceleration at birth and school age was associated with blood pressure and vascular structure and function, measured as carotid intima-media thickness and distensibility, respectively, at age 10 years. We found no associations. Our findings do not support the hypothesis that altered epigenetic aging in early life is a biological mechanism underlying cardiovascular risk factors in childhood.

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Epigenome-wide change and variation in DNA methylation in childhood: Trajectories from birth to late adolescence

01/01/2021 - Rosa H Mulder et al. Human Molecular Genetics. LongITools authors: Janine Felix, Vincent Jaddoe - Erasmus MC
Cohort(s): ALSPAC, Generation R

DNA methylation is an important biological process in childhood health and development, but a comprehensive characterisation of genome-wide DNAm trajectories across this age period is currently lacking. In this manuscript, we used data from epigenome-wide association studies in 5,019 blood samples collected at multiple time-points from birth to late adolescence from 2,348 participants of two large independent cohorts to characterize DNAm trajectories over time. We found that DNAm levels change over time in more than half of the DNAm sites and we describe these changes. Our findings support a developmental role for DNA methylation that extends beyond birth into late adolescence and has implications for understanding life-long health and disease. DNAm trajectories can be visualized at http://epidelta.mrcieu.ac.uk.

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Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight

09/03/2021 - NCD Risk Factor Collaboration (NCD-RisC). eLife. LongITools authors: Marjo-Riitta Järvelin and Sylvain Sebert - University of Oulu

Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions.

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Infant weight growth patterns, childhood BMI and arterial health at age 10 years

10/02/2022 - Giulietta S. Monasso et al. Obesity. LongITools authors: Romy Gaillard, Vincent Jaddoe and Janine Felix - Erasmus MC
Cohort(s): Generation R

Infant peak weight velocity and BMI at adiposity peak were associated with carotid intima-media thickness in healthy children aged 10 years, independent of current BMI. Associations of infant weight growth patterns with carotid distensibility were explained by current BMI. Compared with children with normal weight, those with underweight had lower carotid intima-media thickness, whereas those with overweight had lower carotid distensibility at 10 years. These findings are important from an etiological perspective, as they suggest that both infant and childhood weight might be important for arterial health at school age. Follow-up is needed to determine whether these associations lead to adult cardiovascular disease.

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Relationship between glucose homeostasis and obesity in early life—a study of Italian children and adolescents

30/09/2021 - Zhanna Balkhiyarova et al. Human Molecular Genetics. LongITools authors: Zhanna Balkhiyarova, Marika Kaakinen, Anna Ulrich and Inga Prokopenko - University of Surrey

We aimed to test if weighted genetic risk scores (GRSs) for T2D, fasting glucose (FG) and fasting insulin (FI) predict glycaemic traits and if there is a causal relationship between obesity and impaired glucose metabolism in children and adolescents. Our results demonstrate that the glycaemic and T2D risk genetic variants contribute to higher FG and FI levels and decreased beta cell function in children and adolescents. The causal effects of adiposity on increased insulin resistance are detectable from childhood age.

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Maternal and infant prediction of the child BMI trajectories; studies across two generations of Northern Finland Birth Cohorts

11/10/2020 - Rozenn Nedelec et al. International Journal of Obesity. LongITools authors: Rozenn Nedelec, Marjo-Riitta Järvelin and Sylvain Sebert - University of Oulu
Cohort(s): Northern Finland Birth Cohorts

Detrimental maternal factors were consistently associated with a higher risk obesity trajectory in two generations of Finnish birth cohorts, with a greater amplitude of the effects observed in the younger cohort. However, a discordant association between the timing of adiposity peak in relation to adverse BMI trajectories occurred over the course of a generation, adding further evidence of the link between very early mechanisms, in the first months of life, and childhood obesity.

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Cardiovascular health at age five: distribution, determinants and association with neurodevelopment

11/04/2022 - Rachel E. Climie et al. Frontiers in Pediatrics. LongITools authors: Marie-Alines Charles, Barbara Heude, Jean-Philippe Empana and Rachel Climie - National Institute of Medical Research
Cohort(s): EDEN

This study showed that only a third of French children aged 5 years had ideal cardiovascular health, identified modifiable determinants of ideal cardiovascular health, and provides support for a potential association between cardiovascular health and neurodevelopment at a young age.

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Associations of hair cortisol concentrations with cardiometabolic risk factors in childhood

29/05/2021 - Florianne O L Vehmeijer et al. J Clin Endocrinol Metab. LongITools authors: Susana Santos, Vincent Jaddoe and Janine Felix - Erasmus MC
Cohort(s): Generation R

Stress is related to cardiovascular disease in adults. In a population-based study of 2,598 children, we measured hair cortisol levels at age 6 years as a marker of exposure to stress and examined if these were associated with cardiometabolic risk factors, such as blood pressure and lipid levels, at age 10 years. We did not find such associations after taking BMI into account. The associations of biological stress with cardiometabolic risk factors may develop at later ages.

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Body fat, pericardial fat, liver fat and arterial health at age 10 years

04/05/2022 - Giulietta S. Monasso et al. Pediatric Obesity. LongITools authors: Romy Gaillard, Vincent Jaddoe and Janine Felix - Erasmus MC
Cohort(s): Generation R

Body mass index is associated with vascular health in adults and children. Researchers examined associations of general and more specific measures of adiposity with markers of arterial health in 10-year-old children. At school age, lean and fat mass seem to be related to some measures of arterial health. Arterial development might be affected by lean mass, general and specific fat mass.

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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

05/01/2021 - Lagou V. et al. Nature Communications. LongITools authors: Inga Prokopenko, Marika Kaakinen, Anna Ulrich, Nicholas Timpson, Marjo-Riitta Jarvelin - University of Surrey, Imperial College London, University of Bristol

We report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men.

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Risk of Recurrent Pregnancy Loss in the Ukrainian Population Using a Combined Effect of Genetic Variants: A Case-Control Study

05/01/2021 - Eleni M. Loizidou et al. Genes. LongITools authors: Marika Kaakinen and Inga Prokopenko - University of Surrey

By combining 12 genetic variants from loci reflecting the main biological pathways involved in pregnancy maintenance, we had an improved ability to classify women with and without recurrent pregnancy loss. This highlights the potential of genetics in predicting the risk of this complex multifactorial condition in women of reproductive age.

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Functional Effects In Silico Prediction for Androgen Receptor Ligand-Binding Domain Novel I836S Mutation

06/07/2021 - Alexey Rayevsky et al. Life. LongITools authors: Inga Prokopenko - University of Surrey

Over 1000 mutations are described in the androgen receptor (AR) gene. Of those, about 600 were found in androgen insensitivity syndrome (AIS) patients, among which 400 mutations affect the ligand-binding domain (LBD) of the AR protein. Recently, we reported a novel missense mutation c.2507T>G I836S (ClinVarID: 974911) in a patient with complete AIS (CAIS) phenotype. In the present study, our analyses provide evidence that I836S causes disruptions of AR protein functionality and development of CAIS clinical features in patients.

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COVID‐19 mortality in the UK Biobank cohort: revisiting and evaluating risk factors

15/02/2021 - Elliott, J. et al. European Journal of Epidemiology. LongITools authors: Barbara Bodinier, Roel Vermeulen and Marc Chadeau‐Hyam - Imperial College London, Utrecht University
Cohort(s): UK Biobank

Several factors have been identified as driving the risk of COVID-19 mortality using routine/hospital based studies. Using general population studies we investigate the role of demographic, social, lifestyle, biological, medical and environmental data from UK Biobank in relation to COVID-19 and non-COVID-19 deaths.

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Expression Quantitative Trait Locus Mapping in Pulmonary Arterial Hypertension

22/10/2020 - Ulrich A. et al. Genes. LongITools authors: Inga Prokopenko, Anna Ulrich - University of Surrey

We demonstrate the utility of mapping expression quantitative trait loci (eQTL), which is normally done in individuals from a healthy population, in individuals with a disease. We report novel gene – eQTL pairs overlapping GWAS loci which could possibly aid in the biological interpretation of GWAS associations.

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Heterogeneous Effects of Calorie Content and Nutritional Components Underlie Dietary Influence on Pancreatic Cancer Susceptibility

14/07/2020 - James Dooley et al. Cell Reports. LongITools authors: Inga Prokopenko, Anna Ulrich - University of Surrey

Pancreatic cancer is a rare but fatal form of cancer, the fourth highest in absolute mortality. Known risk factors include obesity, diet, and type 2 diabetes; however, the low incidence rate and interconnection of these factors confound the isolation of individual effects. Here, we use epidemiological analysis of prospective human cohorts and parallel tracking of pancreatic cancer in mice to dissect the effects of obesity, diet, and diabetes on pancreatic cancer. Using epidemiological approaches in humans, we find that dietary sugars give a MAD2L1 genotype-dependent increased susceptibility to pancreatic cancer. The translation of these results to a clinical setting could aid in the identification of the at-risk population for screening and potentially harness dietary modification as a therapeutic measure.

Plasma metabolites associated with exposure to perfluoroalkyl substances and risk of type 2 diabetes – A nested case-control study.

01/01/2021 - T. Schillemans et al. Environment International. LongITools authors: Kati Hanhineva, Rikard Landberg and Carl Brunius. - University of Eastern Finland, Chalmers University of Technology

Perfluoroalkyl substances (PFAS) are widespread persistent environmental pollutants. PFAS may impact Type 2 Diabetes (T2D) development, but findings are inconsistent. Using untargeted metabolomics, we found two groups of metabolites (diacylglycerols and glycerophospholipids) that correlated positively with PFAS. However, these two metabolite groups showed opposite associations with T2D risk, which may help to explain the conflicting results found for PFAS and T2D.

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DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures

07/01/2021 - Monica del C. Gomez‐Alonso et al. Clinical Epigenetics. LongITools authors: Sylvain Sebert and Marjo-Riitta Järvelin. - University of Oulu, Imperial College London

The study provides evidence of an independent association between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses. It brings granularity into well‐known associations of DNA methylation with total serum lipids further supporting the need for detailed profiling of lipid-related traits.

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How does childhood maltreatment influence cardiovascular disease? A sequential causal mediation analysis

26/05/2021 - Ana G Soares et al. International Journal of Epidemiology. LongITools authors: Ana G Soares - University of Bristol
Cohort(s): UK Biobank

Although there is a robust association between childhood maltreatment and cardiovascular disease (CVD) risk, the mechanisms underlying this relationship are not yet fully understood. In this study we showed that anxiety/depression, smoking, body mass index (BMI) and inflammation mediated 26%-90% of the association between childhood maltreatment and CVD and the contribution of these mediators differed by type of maltreatment and sex.

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Post-weight loss changes in fasting appetite and energy balance-related hormone concentrations and the effect of the macronutrient content of a weight maintenance diet: a randomised controlled trial

02/12/2020 - Näätänen M. et al. European Journal of Nutrition. LongITools authors: Marjukka Kolehmainen, Mari Näätänen - University of Eastern Finland

The study looked at the effects of the macronutrient composition of diets with differing satiety values on fasting appetite-related hormone concentrations after weight loss and examined whether the hormone secretion adapted to changes in body fat mass and fat-free mass (FFM) during the weight maintenance period (WM). The macronutrient composition of an isoenergetic WM diet did not affect fasting appetite-related hormone concentrations. Leptin and insulin associated with the amount of the reduced fat mass, whereas ghrelin reflected FFM during the first months of the WM.

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