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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Associations of low levels of air pollution with cardiometabolic outcomes and the role of diet quality in individuals with obesity

06/12/2023 - Darren Healy et al. Environmental Research. LongITools authors: Darren Healy, Anna Kårlund, Santtu Mikkonen, Marjukka Kolehmainen - University of Eastern Finland

Air pollutants, especially particulate matter, were found to be associated with cardiometabolic outcomes, even at average concentrations below the recently updated World Health Organisation’s air quality guidelines. Despite the very-low concentrations, diet quality appeared to modify several associations of air pollutants with cardiometabolic outcomes.

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Cohort profile: the Dutch famine birth cohort (DFBC) – a prospective birth cohort study in the Netherlands

04/03/2021 - Bleker L.S. et al. BMJ Open. LongITools authors: Susanne de Rooij and Tessa Roseboom - Amsterdam University Medical Centers, location AMC
Cohort(s): Dutch Famine Birth Cohort

This paper describes the study protocol and results of the Dutch famine birth cohort study investigating the effects of prenatal exposure to famine on health across the life-course.

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Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

05/10/2023 - Robin N. Beaumont et al. Nature Genetics. LongITools authors: Justiina Ronkainen, Sylvain Sebert, Timo Lakka, Janine Felix, Vincent Jaddoe, Marjo-Riitta Järvelin - Erasmus MC, University of Oulu, Imperial College London, University of Eastern Finland

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Understanding the genetic background of placental growth can help in unravelling the mechanisms underlying a healthy placenta. Researchers examined associations of genetic variants with placental weight using genome-wide association studies with genetic data from over 65,000 fetuses, over 61,000 mothers and over 52,000 fathers. They found 40 genetic variants associated with placental weight, used as a proxy for placental growth. Further analyses indicated that higher placental weight is causally associated with pre-eclampsia risk and shorter pregnancy duration.

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Associations of green and blue space exposure in pregnancy with epigenetic gestational age acceleration

11/01/2023 - Marques I. et al. Epigenetics. LongITools authors: Irene Marques, Susana Santos, Vincent Jaddoe and Janine Felix - Erasmus MC
Cohort(s): Generation R

Natural space exposure, such as availability and proximity to vegetation and water bodies, during pregnancy has been associated with offspring health. Epigenetic gestational age acceleration, a discrepancy between clinical and DNA methylation-based gestational age, which is viewed as a measure of “biological” age, may underlie these associations. This study showed that maternal exposure to green and blue spaces during pregnancy is not associated with offspring epigenetic gestational age acceleration.

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Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation

10/03/2023 - Kotsakis Ruehlmann A. et al. Molecular Psychiatry. LongITools authors: Janine Felix - Erasmus MC

Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. The study showed that children whose mothers reported higher levels of stressful life events during pregnancy exhibited differential methylation at a number of sites in the genome. The findings give more insight into potential mechanisms of neurodevelopment in offspring, although associations with health outcomes need to be further studied.

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Fetal exposure to phthalates and bisphenols and DNA methylation at birth: the Generation R Study

10/10/2022 - Sol C.M. et al. Clinical Epigenetics. LongITools authors: Susana Santos, Vincent Jaddoe and Janine Felix. - Erasmus MC
Cohort(s): Generation R

Phthalates and bisphenols are non-persistent endocrine disrupting chemicals that are ubiquitously present in our environment and may have long-lasting health effects following fetal exposure. We examined if changes in DNA methylation are a biological mechanism that underlies these health effects. Although we did not identify genome-wide significant results, we identified some suggestive associations of exposure to a maternal mixture of phthalates and bisphenols in the first and second trimester with DNA methylation in cord blood that need further exploration in larger study samples.

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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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Maternal Diet Quality During Pregnancy and Offspring Hepatic Fat in Early Childhood: The Healthy Start Study

01/04/2023 - Cohen C.C. et al. Journal of Nutrition. LongITools authors: Janine Felix, Leanne Küpers - Erasmus MC

Poorer maternal diet quality during pregnancy is associated with greater offspring susceptibility to hepatic fat in early childhood. Our findings provide insights into potential perinatal targets for prevention of pediatric nonalcoholic fatty liver disease.

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A meta-analysis of epigenome-wide association studies on pregnancy vitamin B12 concentrations and offspring DNA methylation

24/04/2023 - Monasso G.S. et al. Epigenetics. LongITools authors: Vincent Jaddoe and Janine Felix - Erasmus MC

We meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (2,420 mother-child pairs from four cohorts) or in cord blood (1,029 mother-child pairs from two cohorts), with cord blood DNA methylation. Overall, we showed that maternal and newborn vitamin B12 concentrations are associated with DNA methylation at multiple CpGs in offspring blood. Whether this differential DNA methylation underlies associations of vitamin B12 concentrations with child health outcomes, such as birth weight, gestational age, and childhood cognition, should be further examined in future studies.

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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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Fetal and childhood exposure to parental tobacco smoking and arterial health at age 10 years

18/10/2022 - Giulietta S Monasso et al. American Journal of Hypertension. LongITools authors: Janine Felix and Vincent Jaddoe - Erasmus MC

Exposure to parental tobacco smoking in fetal life and childhood was not associated with intima-media thickness and distensibility of the carotid artery, markers of arterial health, at age 10 years.

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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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Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

11/09/2023 - Latha Kadalayil et al. Clinical Epigenetics. LongITools authors: Janine Felix, Vincent Jaddoe and Johanna Lepeule - Erasmus MC, National Institute of Medical Research

In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNA Methylation (DNAm) and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.

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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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Sex-specific effects of prenatal undernutrition on resting-state functional connectivity in the human brain at age 68

01/04/2022 - Boots A. et al. Neurobiology of Aging. LongITools authors: Tessa Roseboom and Susanne de Rooij. - Amsterdam University Medical Centers, location AMC
Cohort(s): Dutch Famine Birth Cohort

Findings from this publication showed that prenatal undernutrition impacts functional connectivity within and between networks in the brain in late life. Exposed men showed patterns of network desegregation fitting with brain ageing.

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Prenatal exposure to the Dutch famine is associated with more self-perceived cognitive problems at 72 years of age

02/03/2022 - Wiegersmaet A.M. al. BMC Geriatrics. LongITools authors: Tessa Roseboom and Susanne de Rooij. - Amsterdam University Medical Centers, location AMC
Cohort(s): Dutch Famine Birth Cohort

Findings from this publication showed that prenatal undernutrition does not only have lasting effects on brain size, but also on its function, with more self-perceived cognitive problems at older age, which also require more medical attention. Also, the effects of undernutrition depend on sex and its timing during gestation.

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Cord blood leptin level and a common variant of its receptor as determinants of the BMI trajectory: The EDEN mother-child cohort

23/06/2022 - Cissé A.H. et al. Pediatric Obesity. LongITools authors: Aminata H. Cissé and Barbara Heude - National Institute of Medical Research
Cohort(s): EDEN

Adiposity peak and rebound are relevant indicators of subsequent obesity and cardiometabolic risk. We analysed the role of leptin measured in cord blood, recognised as marker of neonatal fat mass, and implicated in early postnatal growth. We showed that increased leptin levels in cord blood were associated with lower BMI at adiposity peak and earlier age at adiposity rebound, characterising a high-risk BMI evolution curve for subsequent obesity. Our results suggested that cord blood leptin level could reflect an unfavourable intrauterine environment and may predict a trajectory at risk for subsequent obesity.

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Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

22/03/2022 - Olivia Solomon et al. Mutation Research/Reviews in Mutation Research. LongITools authors: Barbara Huede, Joanna Lepeule, Janine Felix and Vincent Jaddoe. - Erasmus MC, National Institute of Medical Research
Cohort(s): ALSPAC, Generation R

There are sex-specific differences in disease prevalence, age of onset and susceptibility in multiple health conditions such as asthma and metabolic health. Differential DNA methylation may play a role in these differences. Most of those sites had lower methylation levels in males than in females. Of these differentially methylated CpG sites, 68% (31,727) also showed differences in older children ages 5.5-10 years from 8 cohorts (n = 4268). Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes. These large-scale differences in DNA methylation between the sexes may form the basis for a better understanding of the differences in disease characteristics between males and females. The exact biological mechanisms need further study.

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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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Longitudinal associations of DNA methylation and sleep in children: a meta-analysis

05/07/2022 - Sammallahti S et al. Clinical Epigenetics. LongITools authors: Janine Felix and Barbara Huede. - Erasmus MC, National Institute of Medical Research
Cohort(s): ALSPAC, EDEN, GenerationR

In a meta-analysis of epigenome-wide association study results of 11 cohorts at birth and of 8 cohorts in childhood, we found no associations of DNA methylation at birth with parent-reported sleep duration, sleep initiation problems or sleep fragmentation in childhood. An association was found of lower methylation at one site each at birth with longer actigraphy-estimated sleep duration and sleep onset latency. We did not find associations of DNA methylation in childhood with sleep in childhood. The associations found with objectively measured (through actigraphy) sleep can form a basis for future research.

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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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The relationship of life-course patterns of adiposity with type 2 diabetes, depression, and their comorbidity in the Northern Finland Birth Cohort 1966

13/05/2022 - Choudry P. et al. International Journal of Obesity. LongITools authors: Justiina Ronkainen, Rozenn Nedelec, Marjo-Riitta Jarvelin and Sylvain Sebert - University of Oulu, Imperial College London

Overweight since childhood was shown to be a risk factor for type 2 diabetes and co-morbidity between type 2 diabetes and depression, influenced moderately by lifestyle factors in later life. No shared early life adiposity-related risk factors were observed between type 2 diabetes and depression when assessed independently in this Finnish setting.

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Effect of common pregnancy and perinatal complications on offspring metabolic traits across the life course: a multi-cohort study

18/01/2023 - Elhakeem A. et al. BMC Medicine. LongITools Authors: Ahmed Elhakeem, Justiina Ronkainen, Marjo-Riitta Jarvelin, Vincent Jaddoe, Sylvain Sebert - University of Bristol, University of Oulu, Imperial College London, Erasmus MC
Cohort(s): ALSPAC, Generation R, Northern Finland Birth Cohorts

Common pregnancy and perinatal complications may influence multiple metabolic traits in the offspring and these associations might differ with offspring age. However, this study suggests little evidence of wide-spread and long-term impact of common pregnancy and perinatal complications on offspring metabolic traits.

Depression, cardiometabolic disease, and their co-occurrence after childhood maltreatment: an individual participant data meta-analysis including over 200,000 participants

10/03/2023 - Souama C. et al. BMC Medicine. LongITools authors: Janine Felix, Vincent Jaddoe and Karim Lekadir - Erasmus MC, University of Barcelona

Adults with a history of childhood maltreatment suffer more often from depression and cardiometabolic disease than their non-exposed peers. These adults are also three times more likely to have comorbid depression and cardiometabolic disease. Childhood maltreatment may therefore be a clinically relevant indicator connecting poor mental and somatic health. This meta-analysis revealed that adults with a history of childhood maltreatment suffer more often from depression and cardiometabolic disease than their non-exposed peers. These adults are also three times more likely to have comorbid depression and cardiometabolic disease. Childhood maltreatment may therefore be a clinically relevant indicator connecting poor mental and somatic health.

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Keeping It in the Family: Consanguinity Reveals P4HTM as a Novel Syndromic Obesity Gene

21/08/2023 - Janine F. Felix and Struan Grant. Diabetes. LongITools authors: Janine Felix - Erasmus MC

This is a commentary to a published paper by Saeed et al (Saeed S, Ning L, Badreddine A, et al. Biallelic mutations in P4HTM cause syndromic obesity. Diabetes 2023;72:1228–1234), in which we describe the importance of identifying rare genetic variants for severe obesity for customised treatment strategies.

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Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

13/06/2022 - Winkler, T.W., Rasheed, H., Teumer, A. et al. Communications Biology. LongITools authors: Maryam Kavousi and Vincent Jaddoe - Erasmus MC
Cohort(s): Generation R, Rotterdam Study

Poor kidney function, as estimated by a reduced glomerular filtration rate can progress to kidney failure. Risk factors for a poor kidney function include genetic factors and diabetes, but little is known about their interaction. In this meta-analysis of genome-wide association studies we analysed the genetic background of estimated glomerular filtration rate based on serum creatinine, separately in individuals with (N=178,000) and individuals without (N=1,296,000) diabetes. We found differences between those with and those without diabetes at multiple genetic loci, showing the existence of diabetes-only and non-diabetes-only effects.

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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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Using linear and natural cubic splines, SITAR, and latent trajectory models to characterise nonlinear longitudinal growth trajectories in cohort studies

15/03/2022 - Elhakeem A. et al. BMC Medical Research Methodology. LongITools authors: Ahmed Elhakeem - University of Bristol
Cohort(s): ALSPAC

Linear mixed effecrs models with linear and natural cubic splines, SITAR (Super Imposition by Translation and Rotation), and latent trajectory models are useful for describing nonlinear growth trajectories, and these methods can be adapted for other complex traits. Choice of method depends on the research aims, complexity of the trajectory, and available data.

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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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MC3R links nutritional state to childhood growth and the timing of puberty

03/11/2021 - Lam, B.Y.H., Williamson, A., Finer, S. et al. Nature. LongITools authors: Ana Gonçalves Soares and Nic Timpson - University of Bristol
Cohort(s): ALSPAC

It has long been known that humans with good nutrition tend to grow taller and mature more quickly, and that signals about the body’s nutritional health are sent to the hypothalamus, but how this process is controlled has not previously been understood. We showed that the Melanocortin 3 receptor (MC3R) in the brain regulates the rate of linear growth and timing of sexual maturation, which are energy-sensitive processes.

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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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Associations of Arterial Thickness, Stiffness, and Blood Pressure With Brain Morphology in Early Adolescence: A Prospective Population-Based Study

09/11/2023 - Serena Defina et al. Hypertension. LongITools authors: Janine Felix and Vincent Jaddoe. - Erasmus MC
Cohort(s): Generation R

Arterial wall thickness and stiffness, and high blood pressure have been repeatedly associated with poorer brain health. However, previous studies largely focused on mid- or late-life stages. It is unknown whether any arterial health–related brain changes may be observable already in adolescence. In this study, researchers found blood pressure, but not arterial wall thickness and stiffness, is associated with brain structure in early adolescence.

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Mediators of the association between childhood body mass index and educational attainment: Analysis of a UK prospective cohort study

04/05/2023 - Bowman K. et al. Pediatric Obesity. LongITools authors: Ana Gonçalves Soares - University of Bristol
Cohort(s): ALSPAC

Higher BMI in childhood was associated with lower educational attainment in adolescence. The detrimental effect of higher BMI on educational attainment appears to be partly explained by externalizing behaviours, particularly in females.

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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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Bifidobacterium Is Enriched in Gut Microbiome of Kashmiri Women with Polycystic Ovary Syndrome

18/02/2022 - Hassan S. et al. Genes. LongITools authors: Marika A. Kaakinen, Zhanna Balkhiyarova and Inga Prokopenko - University of Surrey

This study supports that there is a relationship between gut microbiome composition and PCOS with links to specific reproductive health metabolic and hormonal predictors in Indian women.

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Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

26/02/2022 - Pervjakova N. et al. Human Molecular Genetics. LongITools authors: Anni Heiskala, Ville Karhunen, Marjo-Riitta Järvelin and Sylvain Sebert - University of Oulu

Through multi-ancestry meta-analysis, researchers identified five loci associated with gestational diabetes mellitus (GDM), four of which that have been previously reported to associate with type 2 diabetes (T2D). Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

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Abuse in Childhood and Cardiometabolic Health in Early Adulthood: Evidence From the Avon Longitudinal Study of Parents and Children

12/12/2021 - Goncalves Soares A., Zimmerman A. et al.
Cohort(s): ALSPAC

We assessed associations between childhood physical, sexual, and psychological abuse and cardiometabolic outcomes at 18 and 25 years using data from 3,223 ALSPAC participants. We found that childhood abuse is associated with negative cardiometabolic outcomes, particularly higher body mass index (BMI) and insulin, even by young adulthood.

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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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Cardiometabolic risk estimation using exposome data and machine learning

12/09/2023 - Angélica Atehortúa et al. International Journal of Medical Informatics. LongITools authors: Angélica Atehortúa, Marina Camacho, Maria Bulgheroni, Valentina Simonetti, Marc Chadeau-Hyam, Janine F. Felix, Sylvain Sebert and Karim Lekadir. - University of Barcelona, Ab.Acus, Erasmus MC, University of Oulu, Imperial College London
Cohort(s): UK Biobank

The human exposome encompasses all exposures that individuals encounter throughout their lifetime. It is now widely acknowledged that health outcomes are influenced not only by genetic factors but also by the interactions between these factors and various exposures. Personalised early risk assessment based on exposome attributes might be a promising tool for identifying individuals at high risk of cardiovascular disease and type 2 diabetes. Our study resulted in an exposome-based machine learning model that predicts the risk of disease by using a large dataset and outperforms a well-established tool, the Framingham risk, and performs comparably to a more integrative model requiring clinical information.

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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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Measurement invariance testing of the patient health questionnaire-9 (PHQ-9) across people with and without diabetes mellitus from the NHANES, EMHS and UK Biobank datasets

01/09/2021 - Nouwen A., Deschênes S.S. et al. Journal of Affective Disorders. LongITools authors: Zhanna Balkhiyarova and Inga Prokopenko - University of Surrey

The prevalence of depression is higher among those with diabetes than in the general population. The Patient Health Questionnaire (PHQ-9) is commonly used to assess depression in people with diabetes, but measurement invariance of the PHQ-9 across groups of people with and without diabetes has not yet been investigated.Results provide support for measurement invariance between groups of people with and without diabetes, using either a one-factor or a two-factor model. While the two-factor solution has a slightly better fit, the one-factor solution is more parsimonious. Depending on research or clinical needs, both factor structures can be used.

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A bidirectional Mendelian randomisation study to evaluate the relationship between body constitution and hearing loss

31/10/2023 - Yiyan He et al. Scientific Reports. LongITools authors: Yiyan He, Anna Pulakka, and Sylvain Sebert - University of Oulu

This paper evaluated the causal relationships between hearing loss and obesity-related traits using a bidirectional Mendelian randomisation study. The evidence was found that age-related hearing impairment was negatively associated with BMI and body fat percentage in the European ancestry adult population.

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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.

Metabolic profiles reflect weight loss maintenance and the composition of diet after very-low-energy diet

16/05/2023 - Mari Näätänen et al. Clinical Nutrition. LongITools authors: Anna Kårlund, Santtu Mikkonen, Anton Klåvus, Otto Savolainen, Kati Hanhineva, Marjukka Kolehmainen, Mari Näätänen - University of Eastern Finland

Food is one of the main environmental exposures. With this study we investigated weight loss induced metabolites could be differentiated from those resulted from food exposures. We investigated after-weight-loss metabolic signatures of two isocaloric 24-wk weight maintenance diets differing in satiety value due to dietary fibre, protein and fat contents and identified metabolite features that associated with successful weight loss maintenance.

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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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Abdominal obesity is a more important causal risk factor for pancreatic cancer than overall obesity

10/05/2023 - Jared G. Maina et al. European Journal of Human Genetics. LongITools authors: Zhanna Balkhiyarova, Anna Ulrich, and Inga Prokopenko - University of Surrey

Researchers assessed the relationship between pancreatic cancer and two distinct measures of obesity, namely total adiposity, using BMI, versus abdominal, using BMI adjusted waist-to-hip ratio (WHRadjBMI) using polygenic scores (PGS) and Mendelian randomization (MR). The study shows that abdominal adiposity measured using WHRadjBMI, is a more important causal risk factor for pancreatic cancer compared to total adiposity, with T2D being a potential driver of this relationship.

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Bi-directional Mendelian randomization and multi-phenotype GWAS show causality and shared pathophysiology between depression and type 2 diabetes

26/07/2023 - Jared G. Maina et al. Diabetes Care. LongITools authors: Zhanna Balkhiyarova, Anna Ulrich, and Inga Prokopenko - University of Surrey

Our study reveals the complexity in the depression-diabetes relationship and our results have important implications for a more efficient prevention of type 2 diabetes from early adulthood when depressive symptoms usually occur.

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Investigating effect modification between childhood maltreatment and genetic risk for cardiovascular disease in the UK Biobank

04/05/2023 - Helena Urquijo et al. PLOS One. LongITools authors: Ana Goncalves Soares - University of Bristol
Cohort(s): UK Biobank

The effects of genetic susceptibility to a higher body mass index (BMI) may be moderately accentuated in individuals exposed to childhood maltreatment. However, gene environment interactions are likely not a major contributor to the excess burden of cardiovascular disease (CVD) experienced by childhood maltreatment victims.

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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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OTHER PUBLICATIONS

A few of our publications cannot be mapped across the life-course. They can be seen in the table below.

PublicationLink
PublicationAnna Cascarano et al. Machine and deep learning for longitudinal biomedical data: a review of methods and applications. Artificial Intelligence Review (2023).Link

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PublicationClayton G., Gonçalves Soares A. at al. A framework for assessing selection and misclassification bias in Mendelian randomization studies: An illustrative example between body mass index and COVID-19. BMJ (2023).Link

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PublicationIman Zarei et al. Tissue-wide metabolomics reveals wide impact of gut microbiota on mice metabolite composition. Scientific Reports (2023).Link

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PublicationFarizah Babu A. et al. Identification and distribution of sterols, bile acids, and acylcarnitines by LC-MS/MS in humans, mice, and pigs – A qualitative analysis. Metabolites (2022).Link

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PublicationForzano F. et al on behalf of the Executive Committee of the European Society of Human Genetics and the Public and Professional Policy Committee of the European Society of Human Genetics. The use of polygenic risk scores in pre-implantation genetic testing: an unproven, unethical practice. European Journal of Human Genetics (2021).Link

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PublicationZhang P. et al. Defining the scope of exposome studies and research needs from a multidisciplinary perspective. Environmental Science & Technology Letters (2021).Link

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PublicationKårlund A. et al. Harnessing Microbes for Sustainable Development: Food Fermentation as a Tool for Improving the Nutritional Quality of Alternative Protein Sources. Nutrients (2020). Link

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