Publications by authors named "Sylvain Sebert"

95 Publications

Cohort Profile: 46 years of follow-up of the Northern Finland Birth Cohort 1966 (NFBC1966).

Int J Epidemiol 2021 Aug 29. Epub 2021 Aug 29.

Northern Finland Birth Cohorts, Infrastructure for Population Studies, Faculty of Medicine, University of Oulu Center for Life Course Health Research, Faculty of Medicine, University of Oulu Research Unit of Clinical Neuroscience, Department of Psychiatry, University of Oulu.

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http://dx.doi.org/10.1093/ije/dyab109DOI Listing
August 2021

Genetic correlation and causal relationships between cardio-metabolic traits and lung function impairment.

Genome Med 2021 Jun 21;13(1):104. Epub 2021 Jun 21.

Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, UK.

Background: Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors.

Methods: We performed three analyses: (1) cardio-metabolic health to lung function association tests in Northern Finland Birth cohort 1966, (2) cross-trait linkage disequilibrium score regression (LDSC) to compare genetic backgrounds and (3) Mendelian randomisation (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from the UK Biobank data or published large-scale genome-wide association studies (N > 82,000).

Results: We observed a negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR), we found associations between type 2 diabetes (T2D) instruments and forced vital capacity (FVC) as well as FEV1/FVC. Body mass index (BMI) instruments were associated to all lung function traits and C-reactive protein (CRP) instruments to FVC. These genetic associations provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure.

Conclusions: The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being attributed to inflammatory mechanisms. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.
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http://dx.doi.org/10.1186/s13073-021-00914-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215837PMC
June 2021

The determinants and longitudinal changes in vitamin D status in middle-age: a Northern Finland Birth Cohort 1966 study.

Eur J Nutr 2021 Jun 17. Epub 2021 Jun 17.

PEDEGO Research Unit, University of Oulu, 90014, Oulu, Finland.

Purpose: Populations living in the Nordic countries are at high risk for vitamin D (VitD) deficiency or insufficiency. To reduce the risk, nationwide interventions based on food fortification and supplementation are being implemented. However, there is limited evidence about the impact of such public health campaigns on target populations.

Methods: We studied an unselected sample of 3650 participants (56.2% females) from the longitudinal Northern Finland Birth Cohort 1966 with repeated measures of serum 25-hydroxyvitamin D [25(OH)D] at ages 31 (1997) and 46 (2012-2013). Timepoints corresponded to the period before and during the food fortification. We examined the effect of VitD intake from the diet and supplementation, body mass index and previous 25(OH)D concentration on 25(OH)D concentration at 46 years using a multivariable linear regression analysis. A 25(OH)D z score adjusted for sex, season, latitude and technical effect was used in the analysis.

Results: We observed an increase of 10.6 nmol/L in 25(OH)D, when the baseline 25(OH)D was 54.3 nmol/L. The prevalence of serum 25(OH)D below < 50 nmol/L was halved. The changes were found for both sexes and were more pronounced in winter compared to summer months. Regular VitD supplementation had a significant positive effect on 25(OH)D at the age of 46, as well as had the dietary intake of fortified dairy products and fish, and the previous 25(OH)D concentration. However, the intake of fat-spreads albeit VitD-fortified, did not predict 25(OH)D.

Conclusion: Our results demonstrated the positive impact of the fortification programme on VitD status in middle-aged population.
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http://dx.doi.org/10.1007/s00394-021-02606-zDOI Listing
June 2021

Epigenome-Wide Association Study Reveals Methylation Loci Associated With Offspring Gestational Diabetes Mellitus Exposure and Maternal Methylome.

Diabetes Care 2021 Sep 11;44(9):1992-1999. Epub 2021 Jun 11.

Inserm U1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France.

Objective: Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure.

Research Design And Methods: We explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring.

Results: We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10) CpG at the cg22790973 probe ( associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (, as well as cg03456133, cg24440941 (), cg20002843 (, cg19107264, and cg11493553 located within the gene and cg17065901 in both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within the gene, known to be involved in insulin resistance during pregnancy.

Conclusions: Our study reveals the potential complexity of the epigenetic transmission between mothers with GDM and their offspring, likely determined by not only GDM exposure but also other factors indicated by maternal epigenetic status, such as maternal metabolic history.
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http://dx.doi.org/10.2337/dc20-2960DOI Listing
September 2021

Early-onset climacterium is not associated with impaired vitamin D status: a population-based study.

Menopause 2021 05 3;28(8):899-908. Epub 2021 May 3.

PEDEGO Research Unit, University of Oulu, Oulu, Finland.

Objective: To investigate vitamin D status in women with the onset of the climacteric phase by age 46 as both early menopause and inadequate vitamin D status may increase the risk of adverse health outcomes.

Methods: A cross-sectional study included 2,544, 46-year-old women from a birth cohort. Women were divided into the following two groups according to their menstrual history and follicle-stimulating hormone (FSH) concentration: 1) climacteric (FSH ≥25 IU/L and amenorrhea ≥4 mo, n = 351) and 2) preclimacteric women (FSH <25 IU/L and having regular/irregular menstrual cycles, n = 2,193). Serum 25-hydroxyvitamin D (25(OH)D) concentrations were compared between the groups. A linear regression model was performed to investigate which factors are associated with 25(OH)D status.

Results: Mean serum 25(OH)D concentrations were higher in climacteric compared with preclimacteric women (68.1 ± 19.8 nmol/L vs 65.2 ± 19.3 nmol/L, P = 0.01). However, in the linear regression model, climacteric status was not associated with 25(OH)D status (multivariable adjusted mean difference 4.5 nmol/L, 95% confidence interval -1.4 to 10.4, P = 0.137). A total of 76 of the climacteric women were using systemic estrogen hormone therapy (HT). In a subanalysis, including only climacteric women, the use of HT was associated with higher 25(OH)D status (multivariable adjusted mean difference 5.9 nmol/L, 95% confidence interval 1.3-10.5, P = 0.013).

Conclusions: The onset of the climacteric phase by age 46 was not associated with inadequate 25(OH)D concentrations, whereas HT use was associated with higher 25(OH)D status in women with early-onset climacterium.
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http://dx.doi.org/10.1097/GME.0000000000001781DOI Listing
May 2021

The EU Child Cohort Network's core data: establishing a set of findable, accessible, interoperable and re-usable (FAIR) variables.

Eur J Epidemiol 2021 May 21;36(5):565-580. Epub 2021 Apr 21.

Department of Social Medicine, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece.

The Horizon2020 LifeCycle Project is a cross-cohort collaboration which brings together data from multiple birth cohorts from across Europe and Australia to facilitate studies on the influence of early-life exposures on later health outcomes. A major product of this collaboration has been the establishment of a FAIR (findable, accessible, interoperable and reusable) data resource known as the EU Child Cohort Network. Here we focus on the EU Child Cohort Network's core variables. These are a set of basic variables, derivable by the majority of participating cohorts and frequently used as covariates or exposures in lifecourse research. First, we describe the process by which the list of core variables was established. Second, we explain the protocol according to which these variables were harmonised in order to make them interoperable. Third, we describe the catalogue developed to ensure that the network's data are findable and reusable. Finally, we describe the core data, including the proportion of variables harmonised by each cohort and the number of children for whom harmonised core data are available. EU Child Cohort Network data will be analysed using a federated analysis platform, removing the need to physically transfer data and thus making the data more accessible to researchers. The network will add value to participating cohorts by increasing statistical power and exposure heterogeneity, as well as facilitating cross-cohort comparisons, cross-validation and replication. Our aim is to motivate other cohorts to join the network and encourage the use of the EU Child Cohort Network by the wider research community.
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http://dx.doi.org/10.1007/s10654-021-00733-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159791PMC
May 2021

Body size during adulthood, but not in childhood, associates with endometriosis, specifically in the peritoneal subtype-population-based life-course data from birth to late fertile age.

Acta Obstet Gynecol Scand 2021 07 13;100(7):1248-1257. Epub 2021 Feb 13.

Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland.

Introduction: Endometriosis is a common gynecological condition causing chronic pain and infertility. Only limited data exist on body size during childhood and adolescence in affected women. A leaner body shape has been associated with endometriosis in adults. However, longitudinal follow-up data from birth to adulthood are lacking. The aim of this study was to assess the association between body size and endometriosis from birth to age 46 years. We also performed in-depth analysis of the endometriosis subtypes.

Material And Methods: This was a population-based study including 96% of the children born in Northern Finland in 1966. Endometriosis case identification was based on (a) the World Health Organization's International Statistical Classification of Diseases code documentation from national hospital discharge registers and (b) self-reported diagnosis. A total of 348 women with endometriosis (203 in subtype analysis) and 3487 women without endometriosis were identified. Pregnancy, birth, and growth data up to adolescence were collected from welfare clinical records. Follow-up data of the Northern Finland Birth Cohort 1966 were collected at ages 14, 31, and 46 years through postal questionnaires and clinical examinations and included height, weight, and waist and hip circumference measurements. The associations between endometriosis and body size were assessed using logistic regression models.

Results: Body sizes in childhood and adolescence were comparable between women developing endometriosis and those not developing endometriosis. On average, the risk for endometriosis was 2% lower for every kilogram of weight (odds ratio [OR] 0.98, 95% CI 0.97-1.00) and 6% lower for every body mass index unit (OR 0.94, 95% CI 0.90-0.99) at age 31. By age 46, a lower risk for peritoneal endometriosis was observed with greater weight (OR 0.95, 95% CI 0.92-0.98), weight gain from age 14 to age 46 years (OR 0.97, 95% CI 0.93-1.00), body mass index (OR 0.90, 95% CI 0.82-0.98), waist circumference (OR 0.95, 95% CI 0.92-0.99), and waist-hip ratio (OR 0.41, 95% CI 0.21-0.78).

Conclusions: This study provides further evidence of the associations between endometriosis and body size and adiposity, specifically in women with peritoneal endometriosis. The associations are evident in adulthood but not in childhood or adolescence.
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http://dx.doi.org/10.1111/aogs.14090DOI Listing
July 2021

Identifying causative mechanisms linking early-life stress to psycho-cardio-metabolic multi-morbidity: The EarlyCause project.

PLoS One 2021 21;16(1):e0245475. Epub 2021 Jan 21.

Empirica Communication and Technology Research, Bonn, Germany.

Introduction: Depression, cardiovascular diseases and diabetes are among the major non-communicable diseases, leading to significant disability and mortality worldwide. These diseases may share environmental and genetic determinants associated with multimorbid patterns. Stressful early-life events are among the primary factors associated with the development of mental and physical diseases. However, possible causative mechanisms linking early life stress (ELS) with psycho-cardio-metabolic (PCM) multi-morbidity are not well understood. This prevents a full understanding of causal pathways towards the shared risk of these diseases and the development of coordinated preventive and therapeutic interventions.

Methods And Analysis: This paper describes the study protocol for EarlyCause, a large-scale and inter-disciplinary research project funded by the European Union's Horizon 2020 research and innovation programme. The project takes advantage of human longitudinal birth cohort data, animal studies and cellular models to test the hypothesis of shared mechanisms and molecular pathways by which ELS shapes an individual's physical and mental health in adulthood. The study will research in detail how ELS converts into biological signals embedded simultaneously or sequentially in the brain, the cardiovascular and metabolic systems. The research will mainly focus on four biological processes including possible alterations of the epigenome, neuroendocrine system, inflammatome, and the gut microbiome. Life-course models will integrate the role of modifying factors as sex, socioeconomics, and lifestyle with the goal to better identify groups at risk as well as inform promising strategies to reverse the possible mechanisms and/or reduce the impact of ELS on multi-morbidity development in high-risk individuals. These strategies will help better manage the impact of multi-morbidity on human health and the associated risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245475PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819604PMC
June 2021

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

Mol Psychiatry 2021 Jun 8;26(6):2148-2162. Epub 2021 Jan 8.

Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33520, Finland.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
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http://dx.doi.org/10.1038/s41380-020-00987-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263810PMC
June 2021

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

Clin Epigenetics 2021 01 7;13(1). Epub 2021 Jan 7.

Center for Life Course Health Research, University of Oulu, Oulu University Hospital, Oulu, Finland.

Background: The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances.

Results: We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations.

Conclusion: Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.
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http://dx.doi.org/10.1186/s13148-020-00957-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789600PMC
January 2021

Maternal haemoglobin levels in pregnancy and child DNA methylation: a study in the pregnancy and childhood epigenetics consortium.

Epigenetics 2021 Jan 11:1-13. Epub 2021 Jan 11.

Department of Immunobiochemistry, National Institute of Perinatology, Mexico City, Mexico.

Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels.
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http://dx.doi.org/10.1080/15592294.2020.1864171DOI Listing
January 2021

Common maternal and fetal genetic variants show expected polygenic effects on risk of small- or large-for-gestational-age (SGA or LGA), except in the smallest 3% of babies.

PLoS Genet 2020 12 7;16(12):e1009191. Epub 2020 Dec 7.

Department of Child Health, School of Medicine, Cardiff University, Cardiff, United Kingdom.

Babies born clinically Small- or Large-for-Gestational-Age (SGA or LGA; sex- and gestational age-adjusted birth weight (BW) <10th or >90th percentile, respectively), are at higher risks of complications. SGA and LGA include babies who have experienced environment-related growth-restriction or overgrowth, respectively, and babies who are heritably small or large. However, the relative proportions within each group are unclear. We assessed the extent to which common genetic variants underlying variation in birth weight influence the probability of being SGA or LGA. We calculated independent fetal and maternal genetic scores (GS) for BW in 11,951 babies and 5,182 mothers. These scores capture the direct fetal and indirect maternal (via intrauterine environment) genetic contributions to BW, respectively. We also calculated maternal fasting glucose (FG) and systolic blood pressure (SBP) GS. We tested associations between each GS and probability of SGA or LGA. For the BW GS, we used simulations to assess evidence of deviation from an expected polygenic model. Higher BW GS were strongly associated with lower odds of SGA and higher odds of LGA (ORfetal = 0.75 (0.71,0.80) and 1.32 (1.26,1.39); ORmaternal = 0.81 (0.75,0.88) and 1.17 (1.09,1.25), respectively per 1 decile higher GS). We found evidence that the smallest 3% of babies had a higher BW GS, on average, than expected from their observed birth weight (assuming an additive polygenic model: Pfetal = 0.014, Pmaternal = 0.062). Higher maternal SBP GS was associated with higher odds of SGA P = 0.005. We conclude that common genetic variants contribute to risk of SGA and LGA, but that additional factors become more important for risk of SGA in the smallest 3% of babies.
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http://dx.doi.org/10.1371/journal.pgen.1009191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721187PMC
December 2020

DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies.

Genome Med 2020 11 25;12(1):105. Epub 2020 Nov 25.

University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, the Netherlands.

Background: DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.

Methods: We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.

Results: DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth P = 1; childhood P = 2.00 × 10; adolescence P = 2.10 × 10).

Conclusions: There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.
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http://dx.doi.org/10.1186/s13073-020-00810-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687793PMC
November 2020

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

PLoS Genet 2020 10 12;16(10):e1008718. Epub 2020 Oct 12.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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http://dx.doi.org/10.1371/journal.pgen.1008718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581004PMC
October 2020

Maternal and infant prediction of the child BMI trajectories; studies across two generations of Northern Finland birth cohorts.

Int J Obes (Lond) 2021 02 11;45(2):404-414. Epub 2020 Oct 11.

Center for Life Course Health Research, University of Oulu, Oulu, Finland.

Background/objective: Children BMI is a longitudinal phenotype, developing through interplays between genetic and environmental factors. Whilst childhood obesity is escalating, we require a better understanding of its early origins and variation across generations to prevent it.

Subjects/methods: We designed a cross-cohort study including 12,040 Finnish children from the Northern Finland Birth Cohorts 1966 and 1986 (NFBC1966 and NFBC1986) born before or at the start of the obesity epidemic. We used group-based trajectory modelling to identify BMI trajectories from 2 to 20 years. We subsequently tested their associations with early determinants (mother and child) and the possible difference between generations, adjusted for relevant biological and socioeconomic confounders.

Results: We identified four BMI trajectories, 'stable-low' (34.8%), 'normal' (44.0%), 'stable-high' (17.5%) and 'early-increase' (3.7%). The 'early-increase' trajectory represented the highest risk for obesity. We analysed a dose-response association of maternal pre-pregnancy BMI and smoking with BMI trajectories. The directions of effect were consistent across generations and the effect sizes tended to increase from earlier generation to later. Respectively for NFBC1966 and NFBC1986, the adjusted risk ratios of being in the early-increase group were 1.08 (1.06-1.10) and 1.12 (1.09-1.15) per unit of pre-pregnancy BMI and 1.44 (1.05-1.96) and 1.48 (1.17-1.87) in offspring of smoking mothers compared to non-smokers. We observed similar relations with infant factors including birthweight for gestational age and peak weight velocity. In contrast, the age at adiposity peak in infancy was associated with the BMI trajectories in NFBC1966 but did not replicate in NFBC1986.

Conclusions: Exposures to adverse maternal predictors were associated with a higher risk obesity trajectory and were consistent across generations. However, we found a discordant association for the timing of adiposity peak over a 20-year period. This suggests the role of residual environmental factors, such as nutrition, and warrants additional research to understand the underlying gene-environment interplay.
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http://dx.doi.org/10.1038/s41366-020-00695-0DOI Listing
February 2021

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

Environ Health Perspect 2020 09 15;128(9):97003. Epub 2020 Sep 15.

Telethon Kids Institute, University of Western Australia, Nedlands, Perth, Western Australia, Australia.

Background: 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. With declining costs for measuring DNA methylation, we aimed to develop a DNA methylation score that can be used on adolescent DNA methylation data and thereby generate a score for cigarette smoke exposure.

Methods: We used machine learning methods to create a score reflecting exposure to maternal smoking during pregnancy. This score is based on peripheral blood measurements of DNA methylation (Illumina's Infinium HumanMethylation450K BeadChip). The score was developed and tested in the Raine Study with data from 995 white 17-y-old participants using 10-fold cross-validation. The score was further tested and validated in independent data from the Northern Finland Birth Cohort 1986 (NFBC1986) (16-y-olds) and 1966 (NFBC1966) (31-y-olds). Further, three previously proposed DNA methylation scores were applied for comparison. The final score was developed with 204 CpGs using elastic net regression.

Results: Sensitivity and specificity values for the best performing previously developed classifier ("Reese Score") were 88% and 72% for Raine, 87% and 61% for NFBC1986 and 72% and 70% for NFBC1966, respectively; corresponding figures using the elastic net regression approach were 91% and 76% (Raine), 87% and 75% (NFBC1986), and 72% and 78% for NFBC1966.

Conclusion: We have developed a DNA methylation score for exposure to maternal smoking during pregnancy, outperforming the three previously developed scores. 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. Further, it may provide a biomarker for fetal exposure to maternal smoking. https://doi.org/10.1289/EHP6076.
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http://dx.doi.org/10.1289/EHP6076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491641PMC
September 2020

The association between diabetes and cognitive changes during aging.

Scand J Prim Health Care 2020 Sep 10;38(3):281-290. Epub 2020 Aug 10.

Centre for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.

Background: Worldwide, we are observing a rising prevalence of dementia and mild cognitive impairments that often co-occur with the heightened incidence of non-communicable diseases in the elderly. It is suggested that type 2 diabetes and defects in glucose metabolism might predispose to poorer cognitive performances and more rapid decline in old age.

Methods: to address existing knowledge gaps in this area, we systematically reviewed the literature to identify whether patients with type 2 diabetes (T2DM) and pre-diabetes are at a higher risk of poorer cognitive performance, and whether the risk (if any) might affect specific cognitive abilities. We concentrated the review on elderly individuals (65 years or older) at intake. In total, 3251 original articles were retrieved, of which 17 met our inclusion and quality control criteria, which comprised 12 structured questions used to define the articles.

Results: 11 of 17 studies found a statistically significant decline in cognition among individuals who had T2DM or pre-diabetes compared to their non-diabetic counterparts. The association between diabetes and cognitive decline was not always clear, and the extent of the cognitive tests used seemed to have the greatest effect on the results.

Conclusion: Focusing on a population age 65 years and over, we found insufficient evidence to support an association between pre-diabetes stages and mild cognitive impairment. However, there is consistent evidence to support diabetes as an independent risk factor for low cognitive ability in the elderly. Finally, we found insufficient evidence to support effect of T2DM on distinct cognitive ability due to the scarcity of comparable findings.
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http://dx.doi.org/10.1080/02813432.2020.1802140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470088PMC
September 2020

The LifeCycle Project-EU Child Cohort Network: a federated analysis infrastructure and harmonized data of more than 250,000 children and parents.

Eur J Epidemiol 2020 Jul 23;35(7):709-724. Epub 2020 Jul 23.

ISGlobal, Barcelona, Spain.

Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform DataSHIELD, which takes relevant national and international data regulations into account. The EU Child Cohort Network has an open character. All protocols for data harmonization and setting up the data analysis platform are available online. The EU Child Cohort Network creates great opportunities for researchers to use data from different cohorts, during and beyond the LifeCycle Project duration. It also provides a novel model for collaborative research in large research infrastructures with individual-level data. The LifeCycle Project will translate results from research using the EU Child Cohort Network into recommendations for targeted prevention strategies to improve health trajectories for current and future generations by optimizing their earliest phases of life.
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http://dx.doi.org/10.1007/s10654-020-00662-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387322PMC
July 2020

Understanding the cumulative risk of maternal prenatal biopsychosocial factors on birth weight: a DynaHEALTH study on two birth cohorts.

J Epidemiol Community Health 2020 11 24;74(11):933-941. Epub 2020 Jun 24.

Center for Life Course Health Research, University of Oulu, Oulu, Finland

Background: There are various maternal prenatal biopsychosocial (BPS) predictors of birth weight, making it difficult to quantify their cumulative relationship.

Methods: We studied two birth cohorts: Northern Finland Birth Cohort 1986 (NFBC1986) born in 1985-1986 and the Generation R Study (from the Netherlands) born in 2002-2006. In NFBC1986, we selected variables depicting BPS exposure in association with birth weight and performed factor analysis to derive latent constructs representing the relationship between these variables. In Generation R, the same factors were generated weighted by loadings of NFBC1986. Factor scores from each factor were then allocated into tertiles and added together to calculate a cumulative BPS score. In all cases, we used regression analyses to explore the relationship with birth weight corrected for sex and gestational age and additionally adjusted for other factors.

Results: Factor analysis supported a four-factor structure, labelled closely to represent their characteristics as 'Factor1-BMI' (body mass index), 'Factor2-DBP' (diastolic blood pressure), 'Factor3-Socioeconomic-Obstetric-Profile' and 'Factor4-Parental-Lifestyle. In both cohorts, 'Factor1-BMI' was positively associated with birth weight, whereas other factors showed negative association. 'Factor3-Socioeconomic-Obstetric-Profile' and 'Factor4-Parental-Lifestyle' had the greatest effect size, explaining 30% of the variation in birth weight. Associations of the factors with birth weight were largely driven by 'Factor1-BMI'. Graded decrease in birth weight was observed with increasing cumulative BPS score, jointly evaluating four factors in both cohorts.

Conclusion: Our study is a proof of concept for maternal prenatal BPS hypothesis, highlighting the components snowball effect on birth weight in two different European birth cohorts.
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http://dx.doi.org/10.1136/jech-2019-213154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577640PMC
November 2020

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

BMC Public Health 2020 May 18;20(1):708. Epub 2020 May 18.

Center for Life Course Health Research, University of Oulu, P.O.Box 5000, Fin-90014, Oulu, Finland.

Background: The study aimed to explore the association between early life and life-course exposure to social disadvantage and later life body mass index (BMI) accounting for genetic predisposition and maternal BMI.

Methods: We studied participants of Helsinki Birth Cohort Study born in 1934-1944 (HBCS1934-1944, n = 1277) and Northern Finland Birth Cohorts born in 1966 and 1986 (NFBC1966, n = 5807, NFBC1986, n = 6717). Factor analysis produced scores of social disadvantage based on social and economic elements in early life and adulthood/over the life course, and was categorized as high, intermediate and low. BMI was measured at 62 years in HBCS1934-1944, at 46 years in NFBC1966 and at 16 years in NFBC1986. Multivariable linear regression analysis was used to explore associations between social disadvantages and BMI after adjustments for polygenic risk score for BMI (PRS BMI), maternal BMI and sex.

Results: The association between exposure to high early social disadvantage and increased later life BMI persisted after adjustments (β = 0.79, 95% CI, 0.33, 1.25, p < 0.001) in NFBC1966. In NFBC1986 this association was attenuated by PRS BMI (p = 0.181), and in HBCS1934-1944 there was no association between high early social disadvantage and increased later life BMI (β 0.22, 95% CI -0.91,1.35, p = 0.700). In HBCS1934-1944 and NFBC1966, participants who had reduced their exposure to social disadvantage during the life-course had lower later life BMI than those who had increased their exposure (β - 1.34, [- 2.37,-0.31], p = 0.011; β - 0.46, [- 0.89,-0.03], p = 0.038, respectively).

Conclusions: High social disadvantage in early life appears to be associated with higher BMI in later life. Reducing exposure to social disadvantage during the life-course may be a potential pathway for obesity reduction.
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http://dx.doi.org/10.1186/s12889-020-08763-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236362PMC
May 2020

Could vitamin D reduce obesity-associated inflammation? Observational and Mendelian randomization study.

Am J Clin Nutr 2020 05;111(5):1036-1047

Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.

Background: Obesity is associated with inflammation but the role of vitamin D in this process is not clear.

Objectives: We aimed to assess the associations between serum 25-hydroxyvitamin D [25(OH)D], BMI, and 16 inflammatory biomarkers, and to assess the role of vitamin D as a potential mediator in the association between higher BMI and inflammation.

Methods: Northern Finland Birth Cohort 1966 (NFBC1966) 31-y data on 3586 individuals were analyzed to examine the observational associations between BMI, 25(OH)D, and 16 inflammatory biomarkers. Multivariable regression analyses and 2-sample regression-based Mendelian randomization (MR) mediation analysis were performed to assess any role of vitamin D in mediating a causal effect of BMI on inflammatory biomarkers [soluble intercellular adhesion molecule 1 (sICAM-1), high sensitivity C-reactive protein (hs-CRP), and α1-acid glycoprotein (AGP)] for which observational associations were detected. For MR, genome-wide association study summary results ranging from 5163 to 806,834 individuals were used for biomarkers, 25(OH)D, and BMI. Findings were triangulated with a literature review of vitamin D supplementation trials.

Results: In NFBC1966, mean BMI (kg/m2) was 24.8 (95% CI: 24.7, 25.0) and mean 25(OH)D was 50.3 nmol/L (95% CI: 49.8, 50.7 nmol/L). Inflammatory biomarkers correlated as 4 independent clusters: interleukins, adhesion molecules, acute-phase proteins, and chemokines. BMI was positively associated with 9 inflammatory biomarkers and inversely with 25(OH)D (false discovery rate < 0.05). 25(OH)D was inversely associated with sICAM-1, hs-CRP, and AGP, which were positively associated with BMI. The MR analyses showed causal association of BMI on these 3 inflammatory biomarkers. There was no observational or MR evidence that circulating 25(OH)D concentrations mediated the association between BMI and these 3 inflammatory markers. Review of randomized controlled trials (RCTs) supported our findings showing no impact of vitamin D supplementation on inflammatory biomarkers.

Conclusions: The findings from our observational study and causal MR analyses, together with data from RCTs, do not support a beneficial role of vitamin D supplementation on obesity-related inflammation.
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http://dx.doi.org/10.1093/ajcn/nqaa056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198294PMC
May 2020

Possible Modifiers of the Association Between Change in Weight Status From Child Through Adult Ages and Later Risk of Type 2 Diabetes.

Diabetes Care 2020 05 5;43(5):1000-1007. Epub 2020 Mar 5.

Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark.

Objective: We investigated the association between changes in weight status from childhood through adulthood and subsequent type 2 diabetes risks and whether educational attainment, smoking, and leisure time physical activity (LTPA) modify this association.

Research Design And Methods: Using data from 10 Danish and Finnish cohorts including 25,283 individuals, childhood BMI at 7 and 12 years was categorized as normal or high using age- and sex-specific cutoffs (<85th or ≥85th percentile). Adult BMI (20-71 years) was categorized as nonobese or obese (<30.0 or ≥30.0 kg/m, respectively). Associations between BMI patterns and type 2 diabetes (989 women and 1,370 men) were analyzed using Cox proportional hazards regressions and meta-analysis techniques.

Results: Compared with individuals with a normal BMI at 7 years and without adult obesity, those with a high BMI at 7 years and adult obesity had higher type 2 diabetes risks (hazard ratio [HR] 5.04 [95% CI 3.92-6.48]; HR 3.78 [95% CI 2.68-5.33]). Individuals with a high BMI at 7 years but without adult obesity did not have a higher risk (HR 0.74 [95% CI 0.52-1.06]; HR 0.93 [95% CI 0.65-1.33]). Education, smoking, and LTPA were associated with diabetes risks but did not modify or confound the associations with BMI changes. Results for 12 years of age were similar.

Conclusions: A high BMI in childhood was associated with higher type 2 diabetes risks only if individuals also had obesity in adulthood. These associations were not influenced by educational and lifestyle factors, indicating that BMI is similarly related to the risk across all levels of these factors.
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http://dx.doi.org/10.2337/dc19-1726DOI Listing
May 2020

Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age.

Genome Med 2020 03 2;12(1):25. Epub 2020 Mar 2.

Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, QC, Canada.

Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children.

Methods: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung.

Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels.

Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
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http://dx.doi.org/10.1186/s13073-020-0716-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050134PMC
March 2020

Glucose metabolism in midlife predicts participation in working life: a Northern Finland Birth Cohort 1966 study.

Occup Environ Med 2020 05 20;77(5):324-332. Epub 2020 Jan 20.

Center for Life Course Health Research, University of Oulu, Oulu, Finland.

Objective: To evaluate how clinically measured glucose metabolism categories predict registered participation in working life.

Methods: In the 46-year follow-up of Northern Finland Birth Cohort 1966 (n=5328, 2342 men and 2986 women), we used oral glucose tolerance tests, surveys and glycated haemoglobin to determine glucose metabolism categorised as normal, pre-diabetes, screen-detected and previous type 2 diabetes (T2D). Consequent participation in working life during the 2-year follow-up period was measured as registered disability, unemployment and employment days, for which incidence rate ratios (IRRs) with 95% CIs were calculated using Poisson regression, adjusted for baseline employment and socioeconomic, health-related and behavioural factors.

Results: In comparison to normal glucose, all categories of impaired glucose metabolism were associated with poorer participation in working life in the unadjusted models. After adjustments, the risks (IRR (95% CI)) of disability days remained heightened by both screen-detected and previous T2D among men (1.3 (1.3 to 1.4) and 1.5 (1.4 to 1.5), respectively), whereas among women the risks were lowered (0.9 (0.8 to 0.9) and 0.9 (0.9 to 1.0), respectively). The risks of unemployment were consistently higher in all categories of impaired glucose metabolism, and were the highest among women with previous T2D (1.6 (1.5 to 1.6)). Correspondingly, the rates of total employment days were lower in relation to screen-detected T2D among men and women (5% and 6%, respectively), and previous T2D (6% and 3%).

Conclusions: Overall, impaired glucose metabolism associated with deteriorated working life participation already in middle age. The high prevalence of impaired glucose metabolism emphasises the need for actions to support sustainable working careers.
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http://dx.doi.org/10.1136/oemed-2019-106170DOI Listing
May 2020

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Sci Adv 2019 09 4;5(9):eaaw3095. Epub 2019 Sep 4.

Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
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http://dx.doi.org/10.1126/sciadv.aaw3095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904961PMC
September 2019

Investigation of antihypertensive class, dementia, and cognitive decline: A meta-analysis.

Neurology 2020 01 11;94(3):e267-e281. Epub 2019 Dec 11.

From Neuroscience Research Australia (R.P., K.J.A.); University of New South Wales (R.P., C.A., H.B., J.C., P.S.S., K.J.A.), Sydney, Australia; Johns Hopkins University (S.Y., M.C.C.), Baltimore, MD; The George Institute for Global Health (C.A., J.C.), Sydney, Australia; The George Institute China at Peking University Health Sciences Center (C.A.), Beijing, China; Icahn School of Medicine at Mount Sinai (S.A.), New York, NY; Center for Life Course Health Research/Geriatrics (R.A., S.K.-K., S.S., E.V.), University of Oulu; Medical Research Center Oulu (R.A.), Oulu University Hospital; Oulu City Hospital (R.A.), Finland; Department of Preventive Medicine and Public Health (H.A.), Fukuoka University, Japan; Guys and St Thomas' NHS Foundation Trust (N.B.), London, UK; University of Pittsburgh (J.C.B., M.G.), PA; Leiden University Medical Centre (A.S.B., S.T.), the Netherlands; University of Sheffield (A.B., J.P.), UK; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology (M.v.B., S.K.), Maastricht University, the Netherlands; University of Cambridge (C.B.), UK; University of California (M.C., C.K.), Irvine; University of Florida (S.D.), Gainesville; Albert Einstein College of Medicine (C.D., M.K.), New York, NY; University of Alberta (R.A.D., G.P.M.), Edmonton, Canada; International Longevity Centre (F.F.), Paris, France; University of Amsterdam (W.A.v.G., E.P.M.v.C.), the Netherlands; Golgi Cenci Foundation (A.G., R.V.), Milan, Italy; Trinity College Dublin (A.H., R.A.K.), Ireland; University of Calgary (D.B.H.), Canada; Newcastle University (C.J., B.C.M.S.), Newcastle upon Tyne; University of Bristol (P.G.K., S.K.K.), UK; University of Eastern Finland (J.L.), Kuopio; Faculty of Sport and Health Sciences, University of Jyväskylä (J.L.), Finland; School of Pharmacy, University of Waterloo (C.M.), Ontario, Canada; Academic Medical Center (T.v.M., E.R.), Amsterdam; Donders Institute for Brain, Cognition and Behaviour (T.v.M., E.R.), Radboud University Medical Center, Nijmegen, the Netherlands; National University of Singapore (T.-P.N.); Sengkang General Hospital (I.R.), Singhealth Duke-NUS Academic Medical Centre, Singapore; Dalhousie University (K.R.), Halifax, Canada; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy (L.R., I.S.), and Department of Psychology (J.S.), Centre for Ageing and Health (AgeCap) at the University of Gothenburg, Sweden; University of Leuven (J.A.S., L.T.), Belgium; Bordeaux Population Health Research Center (P.J.T., C.T.), UMR 1219, CHU Bordeaux, University of Bordeaux, Inserm, France; University of Adelaide (P.J.T.); Australian National University (E.W.), Canberra, Australia; and University of Warwick (J.W.), Coventry, UK.

Objective: High blood pressure is one of the main modifiable risk factors for dementia. However, there is conflicting evidence regarding the best antihypertensive class for optimizing cognition. Our objective was to determine whether any particular antihypertensive class was associated with a reduced risk of cognitive decline or dementia using comprehensive meta-analysis including reanalysis of original participant data.

Methods: To identify suitable studies, MEDLINE, Embase, and PsycINFO and preexisting study consortia were searched from inception to December 2017. Authors of prospective longitudinal human studies or trials of antihypertensives were contacted for data sharing and collaboration. Outcome measures were incident dementia or incident cognitive decline (classified using the reliable change index method). Data were separated into mid and late-life (>65 years) and each antihypertensive class was compared to no treatment and to treatment with other antihypertensives. Meta-analysis was used to synthesize data.

Results: Over 50,000 participants from 27 studies were included. Among those aged >65 years, with the exception of diuretics, we found no relationship by class with incident cognitive decline or dementia. Diuretic use was suggestive of benefit in some analyses but results were not consistent across follow-up time, comparator group, and outcome. Limited data precluded meaningful analyses in those ≤65 years of age.

Conclusion: Our findings, drawn from the current evidence base, support clinical freedom in the selection of antihypertensive regimens to achieve blood pressure goals.

Clinical Trials Registration: The review was registered with the international prospective register of systematic reviews (PROSPERO), registration number CRD42016045454.
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http://dx.doi.org/10.1212/WNL.0000000000008732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108807PMC
January 2020

Vitamin D Levels in Women with Polycystic Ovary Syndrome: A Population-Based Study.

Nutrients 2019 Nov 19;11(11). Epub 2019 Nov 19.

PEDEGO Research Unit (Research Unit for Pediatrics, Dermatology, Clinical Genetics, Obstetrics and Gynecology), University of Oulu, 90014 Oulu, Finland.

Background: Conflicting evidence supports a role for vitamin D in women with reproductive disorders such as polycystic ovary syndrome (PCOS) but studies on large, unselected populations have been lacking.

Methods: We conducted a general population-based study from the prospective Northern Finland Birth Cohort 1966 (NFBC1966). Serum 25-hydroksyvitamin D (25(OH)D) levels were evaluated in women with self-reported PCOS ( = 280) versus non-symptomatic controls ( = 1573) at the age of 31 with wide range of endocrine and metabolic confounders.

Results: The levels of 25(OH)D were similar among women with and without self-reported PCOS (50.35 vs. 48.30 nmol/L, = 0.051). Women with self-reported PCOS presented with a higher body mass index (BMI), increased insulin resistance, and low-grade inflammation and testosterone levels compared to controls. The adjusted linear regression model showed a positive association between total 25(OH)D levels in self-reported PCOS (β = 2.46, 95% confidence interval (CI) 0.84 to 4.08, = 0.003). The result remained after adjustment for BMI, testosterone, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hs-CRP) levels.

Conclusion: In this population-based setting, PCOS was associated with higher vitamin D levels when adjusting for confounding factors, without distinct beneficial effects on metabolic derangements.
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http://dx.doi.org/10.3390/nu11112831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893754PMC
November 2019

Effect of Sex and Underlying Disease on the Genetic Association of QT Interval and Sudden Cardiac Death.

J Am Heart Assoc 2019 12 21;8(23):e013751. Epub 2019 Nov 21.

Department of Genetic Medicine McKusick-Nathans Institute Johns Hopkins Baltimore MD.

Background Sudden cardiac death (SCD) accounts for ≈300 000 deaths annually in the United States. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease, while women are more likely to have arrhythmic events in the setting of inherited or acquired QT prolongation. Moreover, there is evidence of sex differences in the genetics of QT interval duration. Using sex- and coronary artery disease-stratified analyses, we assess differences in genetic association between longer QT interval and SCD risk. Methods and Results We examined 2282 SCD subjects and 3561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic versus nonischemic) and by sex. We used logistic regression to test for association between the top QT interval-associated single-nucleotide polymorphism, rs12143842 (in the locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups. No statistically significant differences were observed between the sexes for associations with rs12143842, despite the odds ratio being higher in females across all subgroup analyses. Consistent with our hypothesis, female non-ischemics had the highest odds ratio point estimate for association between rs12143842 and SCD risk and male ischemics the lowest odds ratio point estimate (=0.036 for difference). Similar trends were observed for the Mendelian randomization analysis. Conclusions While individual subgroup comparisons did not achieve traditional criteria for statistical significance, this study is consistent with the hypothesis that the causal association of longer QT interval on SCD risk is stronger in women and nonischemic individuals.
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http://dx.doi.org/10.1161/JAHA.119.013751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912973PMC
December 2019
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