Publications by authors named "Katri Raikkonen"

326 Publications

Associations Between Maternal Depression, Antidepressant Use During Pregnancy, and Adverse Pregnancy Outcomes: An Individual Participant Data Meta-analysis.

Obstet Gynecol 2021 Oct;138(4):633-646

Department for Health Evidence, Radboud Institute for Health Sciences, and the Radboud REshape Innovation Center, Radboud University Medical Center, Nijmegen, the Netherlands; the Environmental Research Group, King's College, London, United Kingdom; the Department of Clinical Science, Obstetrics and Gynecology, Umeå University, Umeå, Sweden; the Singapore Institute for Clinical Sciences, Singapore; the Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel; the Department of Child and Adolescent Psychiatry, the Department of Psychology, Education and Child Studies, Erasmus School of Social and Behavioral Sciences, and the Department of Pediatrics, Erasmus University Rotterdam, Rotterdam, the Netherlands; the Department of Pharmacy (Centre IMAGe), Centre Hospitalier Universitaire Sainte-Justine and Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada; the Division of Reproductive and Perinatal Health, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; the Department of Health Science, Medical Faculty, Lund University, Lund, Sweden; the Vincent van Gogh Institute for Psychiatry, Venlo, the Netherlands; the Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan; the Department of Obstetrics & Gynecology, NorthShore University HealthSystem, and the University of Chicago Pritzker School of Medicine, Chicago, Illinois; the School of Public Health and the Irish Centre for Fetal and Neonatal Translational Research (INFANT), University College Cork, Cork, Ireland; the London School of Hygiene and Tropical Medicine, London, United Kingdom; the Elisabeth TweeSteden Hospital (ETZ), Tilburg, the Netherlands; the Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland; the Bradford Teaching Hospitals NHS Foundation Trust, Bradford, United Kingdom; Wayne State University, Detroit, Michigan; the Department of Public Health Science, Karolinska Institutet, Stockholm, Sweden; the PharmacoEpidemiology & Drug Safety Research Group, School of Pharmacy, University of Oslo, and the Department of Child Health and Development, Norwegian Institute of Public Health, Oslo, Norway; the Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire; the University of York, York, United Kingdom; the Faculty of Health, School of Nursing, York University, Toronto, Ontario, Canada; the Department of Psychiatry, University of Necmettin Erbakan, Meram Faculty of Medicine, Konya, Turkey; the School of Nursing and Midwifery, Aga Khan University, Karachi, Pakistan; the Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota; the Department of Psychiatry and Mental Health, University of Cape Town, and the South African Medical Research Council, Unit on Risk and Resilience in Mental Disorders, Cape Town, South Africa; the Charles Perrens Hospital and the Bordeaux Population Health Center, INSERM 1219, Bordeaux University, Bordeaux, France; the Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; the "Alexandra" General Hospital of Athens, Athens, Greece; the Department of Public and Occupational Health, Amsterdam Public Health Research Institute, Academic Medical Center - University of Amsterdam, Amsterdam, the Netherlands; the STIS and Clinical Pharmacology Service, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; the Department of Medical Psychology, Radboud Institute for Health Sciences, and the Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands.

Objective: To evaluate the associations of depressive symptoms and antidepressant use during pregnancy with the risks of preterm birth, low birth weight, small for gestational age (SGA), and low Apgar scores.

Data Sources: MEDLINE, EMBASE, ClinicalTrials.gov, and PsycINFO up to June 2016.

Methods Of Study Selection: Data were sought from studies examining associations of depression, depressive symptoms, or use of antidepressants during pregnancy with gestational age, birth weight, SGA, or Apgar scores. Authors shared the raw data of their studies for incorporation into this individual participant data meta-analysis.

Tabulation, Integration, And Results: We performed one-stage random-effects meta-analyses to estimate odds ratios (ORs) with 95% CIs. The 215 eligible articles resulted in 402,375 women derived from 27 study databases. Increased risks were observed for preterm birth among women with a clinical diagnosis of depression during pregnancy irrespective of antidepressant use (OR 1.6, 95% CI 1.2-2.1) and among women with depression who did not use antidepressants (OR 2.2, 95% CI 1.7-3.0), as well as for low Apgar scores in the former (OR 1.5, 95% CI 1.3-1.7), but not the latter group. Selective serotonin reuptake inhibitor (SSRI) use was associated with preterm birth among women who used antidepressants with or without restriction to women with depressive symptoms or a diagnosis of depression (OR 1.6, 95% CI 1.0-2.5 and OR 1.9, 95% CI 1.2-2.8, respectively), as well as with low Apgar scores among women in the latter group (OR 1.7, 95% CI 1.1-2.8).

Conclusion: Depressive symptoms or a clinical diagnosis of depression during pregnancy are associated with preterm birth and low Apgar scores, even without exposure to antidepressants. However, SSRIs may be independently associated with preterm birth and low Apgar scores.

Systematic Review Registration: PROSPERO, CRD42016035711.
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http://dx.doi.org/10.1097/AOG.0000000000004538DOI Listing
October 2021

Maternal education and cognitive development in 15 European very-preterm birth cohorts from the RECAP Preterm platform.

Int J Epidemiol 2021 Sep 15. Epub 2021 Sep 15.

Department of Pediatrics and Adolescent Medicine, Turku University Hospital Turku, Turku, Finland.

Background: Studies are sparse and inconclusive about the association between maternal education and cognitive development among children born very preterm (VPT). Although this association is well established in the general population, questions remain about its magnitude among children born VPT whose risks of medical and developmental complications are high. We investigated the association of maternal education with cognitive outcomes in European VPT birth cohorts.

Methods: We used harmonized aggregated data from 15 population-based cohorts of children born at <32 weeks of gestational age (GA) or <1500 g from 1985 to 2013 in 13 countries with information on maternal education and assessments of general development at 2-3 years and/or intelligence quotients between 4 and 15 years. Term-born controls (≥37 weeks of GA) were available in eight cohorts. Maternal education was classified as: low (primary/lower secondary); medium (upper secondary/short tertiary); high (bachelor's/higher). Pooled standardized mean differences (SMDs) in cognitive scores were estimated (reference: high educational level) for children assessed at ages 2-3, 4-7 and 8-15 years.

Results: The study included 10 145 VPT children from 12 cohorts at 2-3 years, 8829 from 12 cohorts at 4-7 years and 1865 children from 6 cohorts at 8-15 years. Children whose mothers had low, compared with high, educational attainment scored lower on cognitive measures [pooled unadjusted SMDs: 2-3 years = -0.32 (95% confidence intervals: -0.43 to -0.21); 4-7 years = -0.57 (-0.67; -0.47); 8-15 years = -0.54 (-0.72; -0.37)]. Analyses by GA subgroups (<27 vs ≥27 weeks) in children without severe neonatal morbidity and term controls yielded similar results.

Conclusions: Across diverse settings and regardless of the degree of prematurity, low maternal education was associated with lower cognition.
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http://dx.doi.org/10.1093/ije/dyab170DOI Listing
September 2021

Effect of High-Dose vs Standard-Dose Vitamin D Supplementation on Neurodevelopment of Healthy Term Infants: A Randomized Clinical Trial.

JAMA Netw Open 2021 Sep 1;4(9):e2124493. Epub 2021 Sep 1.

Psychology/Welfare Sciences, Faculty of Social Sciences, University of Tampere, Tampere, Finland.

Importance: Vitamin D may be important for neurodevelopment. The optimal daily dose of vitamin D for early brain development is not known.

Objectives: To test whether a higher (1200 IU) vs standard (400 IU) dose of vitamin D3 has beneficial effects on neurodevelopment in the first 2 years of life and whether serum 25-hydroxyvitamin D concentration is associated with neurodevelopment.

Design, Setting, And Participants: This double-blind, interventional randomized clinical trial involved healthy infants born full-term between January 1, 2013, and June 30, 2014, at a maternity hospital in Helsinki, Finland, at the 60th northern latitude. Two-year follow-up was conducted by May 30, 2016. Data analysis was by the intention-to-treat principle. Data were analyzed from November 1, 2020, to May 31, 2021.

Interventions: Randomization of 404 infants to receive 400 IU of oral vitamin D3 supplementation daily and 397 infants to receive 1200 IU of oral vitamin D3 supplementation daily from 2 weeks to 24 months of age.

Main Outcomes And Measures: Primary outcomes were child total developmental milestone scores at 12 and 24 months of age measured using the Ages and Stages Questionnaire (total score is calculated as a mean of the 5 subscale scores: total score range, 0-60, where 0 indicates delay in all developmental domains and 60 indicates that the child can master all age-specific skills) as well as externalizing, internalizing, and dysregulation problems and competencies scores at 24 months measured using the Infant-Toddler Social and Emotional Assessment (range 0-2, where 0 indicates no problems or no competencies and 2 indicates a high level of problems or a high level of competencies; variables were standardized to the mean [SD] of 0 [1]). Secondary outcomes were specific skills, problems, and competencies derived from these questionnaires.

Results: Of the 987 families recruited, 495 children were randomly assigned to receive 400 IU of vitamin D3, and 492 children were randomly assigned to receive 1200 IU of vitamin D3. A total of 801 families participated in the follow-up at 12 and/or 24 months, with 404 children (207 girls [51.2%]) in the 400-IU group and 397 children (198 girls [49.9%]) in the 1200-IU group. All children were of Northern European ethnicity. No differences were found between the 400-IU group and the 1200-IU group in the mean (SD) adjusted Ages and Stages Questionnaire total score at 12 months (45.0 [7.1] vs 46.2 [7.9]; mean difference [MD], 1.17 [95% CI, -0.06 to 2.38]) or 24 months (50.9 [5.3] vs 51.5 [5.5]; MD, 0.48 [95% CI, -0.40 to 1.36]). No differences were found between the 400-IU group and the 1200-IU group at 24 months in the mean (SD) adjusted Infant-Toddler Social and Emotional Assessment externalizing domain score (-0.07 [1.00] vs 0.07 [0.98]; MD, 0.15 [95% CI, -0.01 to 0.31]), internalizing domain score (0.04 [1.06] vs -0.02 [0.98]; MD, -0.07 [95% CI, -0.24 to 0.1.0]), dysregulation domain score (-0.00 [1.04] vs 0.02 [0.96]; MD, 0.02 [95% CI, -0.14 to 0.18]), or competencies score (-0.02 [1.02] vs 0.01 [1.02]; MD, 0.03 [95% CI, -0.13 to 0.20]). The 1200-IU group did have a higher risk in the adjusted model of scoring 1.5 SDs or more on the externalizing domain score (odds ratio, 2.33 [95% CI, 1.19-4.56]; P = .01). Levels of serum 25-hydroxyvitamin D were not associated with the primary outcomes.

Conclusions And Relevance: Higher-than-standard vitamin D3 doses provide no systematic benefits for child neurodevelopment up to 2 years of age. However, the potential disadvantageous effects of higher doses could not be fully excluded; even if minimal, the potential nonbeneficial effects of higher-than-standard doses warrant further studies in which both safety and benefits should be evaluated.

Trial Registration: ClinicalTrials.gov Identifier: NCT01723852.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.24493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427371PMC
September 2021

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Nat Genet 2021 09 6;53(9):1311-1321. Epub 2021 Sep 6.

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
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http://dx.doi.org/10.1038/s41588-021-00923-xDOI Listing
September 2021

Betamethasone administration during pregnancy is associated with placental epigenetic changes with implications for inflammation.

Clin Epigenetics 2021 Aug 26;13(1):165. Epub 2021 Aug 26.

Institute of Medical Psychology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health (BIH), Luisenstr. 57, 10117, Berlin, Germany.

Background: Glucocorticoids (GCs) play a pivotal role in fetal programming. Antenatal treatment with synthetic GCs (sGCs) in individuals in danger of preterm labor is common practice. Adverse short- and long-term effects of antenatal sGCs have been reported, but their effects on placental epigenetic characteristics have never been systematically studied in humans.

Results: We tested the association between exposure to the sGC betamethasone (BET) and placental DNA methylation (DNAm) in 52 exposed cases and 84 gestational-age-matched controls. We fine-mapped associated loci using targeted bisulfite sequencing. The association of placental DNAm with gene expression and co-expression analysis on implicated genes was performed in an independent cohort including 494 placentas. Exposure to BET was significantly associated with lower placenta DNAm at an enhancer of FKBP5. FKBP5 (FK506-binding protein 51) is a co-chaperone that modulates glucocorticoid receptor activity. Lower DNAm at this enhancer site was associated with higher expression of FKBP5 and a co-expressed gene module. This module is enriched for genes associated with preeclampsia and involved in inflammation and immune response.

Conclusions: Our findings suggest that BET exposure during pregnancy associates with few but lasting changes in placental DNAm and may promote a gene expression profile associated with placental dysfunction and increased inflammation. This may represent a pathway mediating GC-associated negative long-term consequences and health outcomes in offspring.
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http://dx.doi.org/10.1186/s13148-021-01153-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393766PMC
August 2021

Maternal body mass index in pregnancy and mental disorders in adult offspring: a record linkage study in Aberdeen, Scotland.

Sci Rep 2021 07 23;11(1):15132. Epub 2021 Jul 23.

Centre for Cardiovascular Science and Tommy's Centre for Fetal and Maternal Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.

Maternal obesity in pregnancy predicts offspring psychopathology risk in childhood but it remains unclear whether maternal obesity or underweight associate with adult offspring mental disorders. We examined longitudinally whether maternal body mass index (BMI) in pregnancy predicted mental disorders in her offspring and whether the associations differed by offspring birth year among 68,571 mother-child dyads of Aberdeen Maternity and Neonatal Databank, Scotland. The offspring were born 1950-1999. Maternal BMI was measured at a mean 15.7 gestational weeks and classified into underweight, normal weight, overweight, moderate obesity and severe obesity. Mental disorders were identified from nationwide registers carrying diagnoses of all hospitalizations and deaths in Scotland in 1996-2017. We found that maternal BMI in pregnancy was associated with offspring mental disorders in a time-dependent manner: In offspring born 1950-1974, maternal underweight predicted an increased hazard of mental disorders [Hazard Ratio (HR) = 1.74; 95% Confidence Interval (CI) = 1.01-3.00)]. In offspring born 1975-1999, maternal severe obesity predicted increased hazards of any mental (HR 1.60; 95% CI 1.08-2.38) substance use (HR 1.91; 95% CI 1.03-3.57) and schizophrenia spectrum (HR 2.80; 95% CI 1.40-5.63) disorders. Our findings of time-specific associations between maternal prenatal BMI and adult offspring mental disorders may carry important public health implications by underlining possible lifelong effects of maternal BMI on offspring psychopathology.
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http://dx.doi.org/10.1038/s41598-021-94511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302653PMC
July 2021

Longitudinal metabolic profiling of maternal obesity, gestational diabetes and hypertensive pregnancy disorders.

J Clin Endocrinol Metab 2021 Jun 29. Epub 2021 Jun 29.

Helsinki, Finland; Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Context: Comprehensive assessment of metabolism in maternal obesity and pregnancy disorders can provide information about the shared maternal-fetal milieu and give insight into both maternal long-term health and intergenerational transmission of disease burden.

Objective: To assess levels, profiles and change in the levels of metabolic measures during pregnancies complicated by obesity, gestational diabetes (GDM) or hypertensive disorders.

Design, Setting And Participants: A secondary analysis of two study cohorts, PREDO and RADIEL, including 741 pregnant women.

Main Outcome Measures: We assessed 225 metabolic measures by nuclear magnetic resonance in blood samples collected at median 13 (interquartile range, 12.4-13.7), 20 (19.3-23.0) and 28 (27.0-35.0) weeks of gestation.

Results: Across all three time points women with obesity (body mass index, BMI≥30kg/m 2) in comparison to normal weight (BMI 18.5-24.99 kg/m 2) had significantly higher levels of most very-low-density-lipoprotein-related measures, many fatty and most amino acids and more adverse metabolic profiles. The change in the levels of most metabolic measures during pregnancy was smaller in obese than in normal weight women. GDM, preeclampsia and chronic hypertension were associated with metabolic alterations similar to obesity. The associations of obesity held after adjustment for GDM and hypertensive disorders, but many of the associations with GDM and hypertensive disorders were rendered non-significant after adjustment for BMI and the other pregnancy disorder.

Conclusions: This study shows that the pregnancy-related metabolic change is smaller in women with obesity, who display metabolic perturbations already in early pregnancy. Metabolic alterations of obesity and pregnancy disorders resembled each other suggesting a shared metabolic origin.
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http://dx.doi.org/10.1210/clinem/dgab475DOI Listing
June 2021

Serum Inhibin-A and PAPP-A2 in the prediction of pre-eclampsia during the first and second trimesters in high-risk women.

Pregnancy Hypertens 2021 Aug 2;25:116-122. Epub 2021 Jun 2.

Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Department of Obstetrics and Gynecology, Tampere University Hospital and Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland.

Objectives: Maternal serum inhibin-A, pregnancy associated plasma protein-A (PAPP-A) and PAPP-A2 together with placental growth factor (PlGF), maternal risk factors and uterine artery pulsatility index (UtA PI) were analysed to study their ability to predict pre-eclampsia (PE).

Study Design: Serial serum samples for the nested case-control study were collected prospectively at 12-14, 18-20 and 26-28 weeks of gestation from 11 women who later developed early-onset PE (EO PE, diagnosis < 34 + 0 weeks of gestation), 34 women who developed late-onset PE (LO PE, diagnosis ≥ 34 + 0 weeks) and 89 controls.

Main Outcome Measures: Gestational age -adjusted multiples of the median (MoM) values were calculated for biomarker concentrations. Multivariate regression analyses were performed to combine first trimester biomarkers, previously reported results on PlGF, maternal risk factors and UtA PI. Area under curve (AUC) values and 95% confidence intervals (CIs) for the prediction of PE and its subtypes were calculated.

Results: A high first trimester inhibin-A predicted PE (AUC 0.618, 95%CI, 0.513-0.724), whereas PAPP-A and PlGF predicted only EO PE (0.701, 0.562-0.840 and 0.798, 0.686-0.909, respectively). At 26-28 weeks PAPP-A2 and inhibin-A predicted all PE subtypes. In the multivariate setting inhibin-A combined with maternal pre-pregnancy body mass index, prior PE and mean UtA PI predicted PE (0.811,0.726-0.896) and LO PE (0.824, 0.733-0.914).

Conclusions: At first trimester inhibin-A show potential ability to predict not only EO PE but also LO PE whereas PlGF and PAPP-A predict only EO PE. At late second trimester inhibin-A and PAPP-A2 might be useful for short-term prediction of PE.
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http://dx.doi.org/10.1016/j.preghy.2021.05.024DOI Listing
August 2021

Association of Very Preterm Birth or Very Low Birth Weight With Intelligence in Adulthood: An Individual Participant Data Meta-analysis.

JAMA Pediatr 2021 Aug 2;175(8):e211058. Epub 2021 Aug 2.

Department of Psychology, University of Warwick, Coventry, United Kingdom.

Importance: Birth before 32 weeks' gestation (very preterm [VPT]) and birth weight below 1500 g (very low birth weight [VLBW]) have been associated with lower cognitive performance in childhood. However, there are few investigations of the association of neonatal morbidities and maternal educational levels with the adult cognitive performance of individuals born VPT or VLBW (VPT/VLBW).

Objective: To assess differences in adult IQ between VPT/VLBW and term-born individuals and to examine the association of adult IQ with cohort factors, neonatal morbidities, and maternal educational level among VPT/VLBW participants.

Data Sources: Systematic review of published data from PubMed and meta-analysis of individual participant data (IPD) of cohorts from 2 consortia (Research on European Children and Adults Born Preterm [RECAP] and Adults Born Preterm International Collaboration [APIC]).

Study Selection: The meta-analysis included prospective longitudinal cohort studies that assessed the full-scale IQ of adults born VPT or VLBW and respective control groups comprising term-born adults.

Data Extraction And Synthesis: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline for analyses of individual participant data and identified 8 studies that provided data from 2135 adults (1068 VPT/VLBW and 1067 term-born participants) born between 1978 and 1995. Meta-analyses of IPD were performed using a 1-stage approach, treating VPT birth or VLBW and cohort as random effects.

Main Outcomes And Measures: Full-scale IQ scores were converted to z scores within each cohort using the combined SD of VPT/VLBW participants and a control group of term-born participants, with scores centered on the mean of the control group.

Results: A total of 426 records were identified and screened. After exclusions, 13 studies were included in the aggregate meta-analysis. The IPD meta-analysis included 8 of the 9 RECAP and APIC cohorts with adult IQ data. The mean (SD) age among the 8 IPD cohorts was 24.6 (4.3) years, and 1163 participants (54.5%) were women. In unadjusted analyses, VPT/VLBW participants had mean adult IQ scores that were 0.78 SD (95% CI, -0.90 to -0.66 SD) lower than term-born participants, equivalent to a difference of 12 IQ points. Among VPT/VLBW participants, lower gestational age (score difference per week of gestation, 0.11; 95% CI, 0.07-0.14), lower birth weight z scores (score difference per 1.0 SD, 0.21; 95% CI, 0.14-0.28), the presence of neonatal bronchopulmonary dysplasia (score difference, -0.16; 95% CI, -0.30 to -0.02) or any grade of intraventricular hemorrhage (score difference, -0.19; 95% CI, -0.33 to -0.05), and lower maternal educational level (score difference, 0.26; 95% CI, 0.17-0.35) were all significantly associated with lower IQ scores in adulthood.

Conclusions And Relevance: In this IPD meta-analysis, lower gestational age, lower weight for gestational age, neonatal morbidities, and lower maternal educational levels were all important risk factors associated with lower IQ among young adults born VPT or VLBW.
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http://dx.doi.org/10.1001/jamapediatrics.2021.1058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329745PMC
August 2021

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Neuropsychopharmacology 2021 09 25;46(10):1788-1801. Epub 2021 May 25.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
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http://dx.doi.org/10.1038/s41386-021-01023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357785PMC
September 2021

Maternal Hypertensive Pregnancy Disorders and Mental and Behavioral Disorders in the Offspring: a Review.

Curr Hypertens Rep 2021 05 13;23(5):30. Epub 2021 May 13.

Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Haartmaninkatu 3, P.O. Box 9, FI-00014 University of Helsinki, Helsinki, Finland.

Purpose Of Review: We review here recent original research and meta-analytic evidence on the associations of maternal hypertensive pregnancy disorders and mental and behavioral disorders in the offspring.

Recent Findings: Seven meta-analyses and 11 of 16 original research studies published since 2015 showed significant associations between maternal hypertensive pregnancy disorders and offspring mental and behavioral disorders. Evidence was most consistent in meta-analyses and high-quality cohort studies. The associations, independent of familial confounding, were observed on different mental and behavioral disorders in childhood and schizophrenia in adulthood. Preterm birth and small-for-gestational age birth emerged as possible moderators and mediators of the associations. Cross-sectional and case-control studies yielded inconsistent findings, but had lower methodological quality. Accumulating evidence from methodologically sound studies shows that maternal hypertensive pregnancy disorders are associated with an increased risk of mental and behavioral disorders in the offspring in childhood. More studies on adult mental disorders are needed.
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http://dx.doi.org/10.1007/s11906-021-01141-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116290PMC
May 2021

Characteristics of epigenetic aging across gestational and perinatal tissues.

Clin Epigenetics 2021 04 29;13(1):97. Epub 2021 Apr 29.

Department of Translational Psychiatry, Max Planck Institute of Psychiatry, München, Germany.

Background: Epigenetic clocks have been used to indicate differences in biological states between individuals of same chronological age. However, so far, only few studies have examined epigenetic aging in newborns-especially regarding different gestational or perinatal tissues. In this study, we investigated which birth- and pregnancy-related variables are most important in predicting gestational epigenetic age acceleration or deceleration (i.e., the deviation between gestational epigenetic age estimated from the DNA methylome and chronological gestational age) in chorionic villus, placenta and cord blood tissues from two independent study cohorts (ITU, n = 639 and PREDO, n = 966). We further characterized the correspondence of epigenetic age deviations between these tissues.

Results: Among the most predictive factors of epigenetic age deviations in single tissues were child sex, birth length, maternal smoking during pregnancy, maternal mental disorders until childbirth, delivery mode and parity. However, the specific factors related to epigenetic age deviation and the direction of association differed across tissues. In individuals with samples available from more than one tissue, relative epigenetic age deviations were not correlated across tissues.

Conclusion: Gestational epigenetic age acceleration or deceleration was not related to more favorable or unfavorable factors in one direction in the investigated tissues, and the relative epigenetic age differed between tissues of the same person. This indicates that epigenetic age deviations associate with distinct, tissue specific, factors during the gestational and perinatal period. Our findings suggest that the epigenetic age of the newborn should be seen as a characteristic of a specific tissue, and less as a general characteristic of the child itself.
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http://dx.doi.org/10.1186/s13148-021-01080-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082803PMC
April 2021

Links between television exposure and toddler dysregulation: Does culture matter?

Infant Behav Dev 2021 05 18;63:101557. Epub 2021 Apr 18.

Washington State University, USA. Electronic address:

Television exposure in early childhood has increased, with concerns raised regarding adverse effects on social-emotional development, and emerging self-regulation in particular. The present study addressed television exposure (i.e., amount of time watching TV) and its associations with toddler behavioral/emotional dysregulation, examining potential differences across 14 cultures. The sample consisted of an average of 60 toddlers from each of the 14 countries from the Joint Effort Toddler Temperament Consortium (JETTC; Gartstein & Putnam, 2018). Analyses were conducted relying on the multi-level modeling framework (MLM), accounting for between- and within-culture variability, and examining the extent to which TV exposure contributions were universal vs. variable across sites. Effects of time watching TV were evaluated in relation to temperament reactivity and regulation, as well as measures of emotional reactivity, attention difficulties, and aggression. Results indicated that more time spent watching TV was associated with higher ratings on Negative Emotionality, emotional reactivity, aggression, and attention problems, as well as lower levels of soothability. However, links between TV exposure and both attention problems and soothability varied significantly between cultures. Taken together, results demonstrate that increased time spent watching television was generally associated with dysregulation, although effects were not consistently uniform, but rather varied as a function of culturally-dependent contextual factors.
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http://dx.doi.org/10.1016/j.infbeh.2021.101557DOI Listing
May 2021

An EPIC predictor of gestational age and its application to newborns conceived by assisted reproductive technologies.

Clin Epigenetics 2021 04 19;13(1):82. Epub 2021 Apr 19.

Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.

Background: Gestational age is a useful proxy for assessing developmental maturity, but correct estimation of gestational age is difficult using clinical measures. DNA methylation at birth has proven to be an accurate predictor of gestational age. Previous predictors of epigenetic gestational age were based on DNA methylation data from the Illumina HumanMethylation 27 K or 450 K array, which have subsequently been replaced by the Illumina MethylationEPIC 850 K array (EPIC). Our aims here were to build an epigenetic gestational age clock specific for the EPIC array and to evaluate its precision and accuracy using the embryo transfer date of newborns from the largest EPIC-derived dataset to date on assisted reproductive technologies (ART).

Methods: We built an epigenetic gestational age clock using Lasso regression trained on 755 randomly selected non-ART newborns from the Norwegian Study of Assisted Reproductive Technologies (START)-a substudy of the Norwegian Mother, Father, and Child Cohort Study (MoBa). For the ART-conceived newborns, the START dataset had detailed information on the embryo transfer date and the specific ART procedure used for conception. The predicted gestational age was compared to clinically estimated gestational age in 200 non-ART and 838 ART newborns using MM-type robust regression. The performance of the clock was compared to previously published gestational age clocks in an independent replication sample of 148 newborns from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restrictions (PREDO) study-a prospective pregnancy cohort of Finnish women.

Results: Our new epigenetic gestational age clock showed higher precision and accuracy in predicting gestational age than previous gestational age clocks (R = 0.724, median absolute deviation (MAD) = 3.14 days). Restricting the analysis to CpGs shared between 450 K and EPIC did not reduce the precision of the clock. Furthermore, validating the clock on ART newborns with known embryo transfer date confirmed that DNA methylation is an accurate predictor of gestational age (R = 0.767, MAD = 3.7 days).

Conclusions: We present the first EPIC-based predictor of gestational age and demonstrate its robustness and precision in ART and non-ART newborns. As more datasets are being generated on the EPIC platform, this clock will be valuable in studies using gestational age to assess neonatal development.
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http://dx.doi.org/10.1186/s13148-021-01055-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056641PMC
April 2021

Anti-inflammatory Potential of Maternal Diet During Pregnancy: A Promise to Promote the Mental Health of Children.

Biol Psychiatry 2021 03;89(6):536-538

Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.1016/j.biopsych.2020.12.005DOI Listing
March 2021

Physical Activity, Mental Health, and Well-Being in Very Pre-Term and Term Born Adolescents: An Individual Participant Data Meta-Analysis of Two Accelerometry Studies.

Int J Environ Res Public Health 2021 02 10;18(4). Epub 2021 Feb 10.

Department of Psychology, University of Warwick, Coventry CV4 7AL, UK.

This study examined whether physical activity is associated with better mental health and well-being among very preterm (≤32 weeks) and term born (≥37 weeks) adolescents alike or whether the associations are stronger in either of the groups. Physical activity was measured with accelerometry in children born very preterm and at term in two cohorts, the Basel Study of Preterm Children (BSPC; 40 adolescents born ≤32 weeks of gestation and 59 term born controls aged 12.3 years) and the Millennium Cohort Study (MCS; 45 adolescents born ≤32 weeks of gestation and 3137 term born controls aged 14.2 years on average). In both cohorts, emotional and behavioral problems were mother-reported using the Strengths and Difficulties Questionnaire. Subjective well-being was self-reported using the Kidscreen-52 Questionnaire in the BSPC and single items in the MCS. Hierarchical regressions with 'preterm status × physical activity'-interaction effects were subjected to individual participant data (IPD) meta-analysis. IPD meta-analysis showed that higher levels of physical activity were associated with lower levels of peer problems, and higher levels of psychological well-being, better self-perception/body image, and school related well-being. Overall, the effect-sizes were small and the associations did not differ significantly between very preterm and term born adolescents. Future research may examine the mechanisms behind effects of physical activity on mental health and wellbeing in adolescence as well as which type of physical activity might be most beneficial for term and preterm born children.
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http://dx.doi.org/10.3390/ijerph18041735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916780PMC
February 2021

Combined effects of genotype and childhood adversity shape variability of DNA methylation across age.

Transl Psychiatry 2021 02 1;11(1):88. Epub 2021 Feb 1.

Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804, Munich, Germany.

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.
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http://dx.doi.org/10.1038/s41398-020-01147-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851167PMC
February 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 04;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Presleep physiological stress is associated with a higher cortical arousal in sleep and more consolidated REM sleep.

Stress 2021 Jan 18:1-9. Epub 2021 Jan 18.

Research Program Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

How sleep regulates physiological stress in healthy individuals is not well understood. We explored the associations between naturally occurring pre-sleep physiological arousal and EEG power spectral density together with rapid eye movement sleep (REMS) continuity. One hundred and fifty-four individuals (mean age 16.9, SD 0.1 years) collected five samples of saliva between the evening (mean time 18:20) and bedtime (mean 23:00) by using swabs, and underwent an overnight in-home polysomnography. We calculated spectral density for REMS and non-rapid eye movement sleep (non-REMS), and the number and duration of REMS arousals (<15 s) during sleep. An observational design allowed for measurement of natural variation in physiological and sleep arousal. Increasing cortisol levels toward bedtime were associated with higher EEG power spectral density at all frequency ranges in frontal locations, the highest association being for the beta1 frequency band. In central locations, the associations were pronounced for beta1 and beta2 bands. Higher overall cortisol levels in the evening were associated with less fragmented REMS. Presleep arousal was not associated with sleep staging. Physiological arousal toward bedtime was associated with EEG power spectral density values during sleep specifically at high EEG frequencies. This may represent a compensatory mechanism that serves as an adaptation to stress, since the REMS was more continuous along a higher physiological arousal level in the evening. Although causality cannot be inferred, a design with nonmanipulated physiological stress followed by naturally timed sleep at home provides new insights into stress regulation homeostasis.
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http://dx.doi.org/10.1080/10253890.2020.1869936DOI Listing
January 2021

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

Mol Psychiatry 2021 06 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

Maternal anxiety during pregnancy and newborn epigenome-wide DNA methylation.

Mol Psychiatry 2021 06 7;26(6):1832-1845. Epub 2021 Jan 7.

Erasmus MC, University Medical Center Rotterdam, Generation R Study Group, Rotterdam, The Netherlands.

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.
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http://dx.doi.org/10.1038/s41380-020-00976-0DOI Listing
June 2021

A polyepigenetic glucocorticoid exposure score at birth and childhood mental and behavioral disorders.

Neurobiol Stress 2020 Nov 21;13:100275. Epub 2020 Nov 21.

Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Finland.

Background: Maternal depression and anxiety during pregnancy may enhance fetal exposure to glucocorticoids (GCs) and harm neurodevelopment. We tested whether a novel cross-tissue polyepigenetic biomarker indicative of exposure to GC is associated with mental and behavioral disorders and their severity in children, possibly mediating the associations between maternal prenatal depressive and anxiety symptoms and these child outcomes.

Methods: Children (n = 814) from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) study were followed-up from birth to age 7.1-10.7 years. A weighted polyepigenetic GC exposure score was calculated based on the methylation profile of 24 CpGs from umbilical cord blood. Child diagnosis of mental and behavioral disorder (n = 99) and its severity, defined as the number of days the child had received treatment (all 99 had received outpatient treatment and 8 had been additionally in inpatient treatment) for mental or behavioral disorder as the primary diagnosis, came from the Care Register for Health Care. Mothers (n = 408) reported on child total behavior problems at child's age of 2.3-5.8 years and their own depressive and anxiety symptoms during pregnancy (n = 583).

Results: The fetal polyepigenetic GC exposure score at birth was not associated with child hazard of mental and behavioral disorder (HR = 0.82, 95% CI 0.54; 1.24, p = 0.35) or total behavior problems (unstandardized beta = -0.10, 95% CI -0.31; 0.10, p = 0.33). However, for one standard deviation decrease in the polyepigenetic score, the child had spent 2.94 (95%CI 1.59; 5.45, p < 0.001) more days in inpatient or outpatient treatment with any mental and behavioral disorder as the primary diagnosis. Criteria for mediation tests were not met.

Conclusions: These findings suggest that fetal polyepigenetic GC exposure score at birth was not associated with any mental or behavioral disorder diagnosis or mother-rated total behavior problems, but it may contribute to identifying children at birth who are at risk for more severe mental or behavioral disorders.
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http://dx.doi.org/10.1016/j.ynstr.2020.100275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739178PMC
November 2020

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

The association between sleep-wake ratio and overnight picture recognition is moderated by BDNF genotype.

Neurobiol Learn Mem 2021 01 27;177:107353. Epub 2020 Nov 27.

Sleepwell Research Program, Faculty of Medicine, University of Helsinki, P.O. Box 9, 00014 Helsinki, Finland. Electronic address:

A wealth of studies supports the role of sleep in memory performance. Experimentally controlled studies indicate that prolonged wake after memory encoding is detrimental for memory outcome whereas sleep protects from wake-time interference and promotes memory consolidation. We examined how the natural distribution of wake and sleep between encoding and retrieval associated with overnight picture recognition accuracy among 161 adolescents following their typical sleep schedule with an in-home polysomnography. The memorized pictures varied in their level of arousal (calm to exciting) and valence (negative to positive). Suspecting genotypic influence on the sensitivity for sleep/wake dynamics, we also assessed if these associations were affected by known gene polymorphisms involved in neural plasticity and sleep homeostasis: brain-derived neurotrophic factor (BDNF) Val66Met and Catechol-O-methyltransferase (COMT) Val158Met. In the whole sample, overnight recognition accuracy was associated with the levels of arousal and valence of the pictures, but not with sleep percentage (i.e. the percentage of time spent asleep between memory encoding and retrieval). While the allelic status of BDNF or COMT did not have any main effect on recognition accuracy, a significant moderation by BDNF Val66Met was found (p = .004): the subgroup homozygous for valine allele showed positive association between sleep percentage and recognition accuracy. This was underlain by detrimental influence of wake, rather than by any memory benefit of sleep. Our results complement the mounting evidence that the relation between sleep and memory performance is moderated by BDNF Val66Met. Further studies are needed to clarify the specific mechanisms.
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http://dx.doi.org/10.1016/j.nlm.2020.107353DOI Listing
January 2021

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

Association between DNA methylation and ADHD symptoms from birth to school age: a prospective meta-analysis.

Transl Psychiatry 2020 11 12;10(1):398. Epub 2020 Nov 12.

Clinical Child & Family Studies, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4-15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance (p < 0.05) in either of the EWAS were correlated between timepoints (ρ = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms (p < 1 × 10), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p < 1 × 10. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.
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http://dx.doi.org/10.1038/s41398-020-01058-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665047PMC
November 2020

Maternal Antenatal Corticosteroid Treatment and Childhood Mental and Behavioral Disorders-Reply.

JAMA 2020 10;324(15):1570-1571

Department of Public Health Solutions, THL Finnish Institute for Health and Welfare, Helsinki.

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http://dx.doi.org/10.1001/jama.2020.15449DOI Listing
October 2020

Common Core Assessments in follow-up studies of adults born preterm-Recommendation of the Adults Born Preterm International Collaboration.

Paediatr Perinat Epidemiol 2021 05 29;35(3):371-387. Epub 2020 Sep 29.

Clinical Sciences, Murdoch Children's Research Institute, Melbourne, Vic., Australia.

Background: Of all newborns, 1%-2% are born very preterm (VP; <32 weeks) or with very low birthweight (VLBW; ≤1500 g). Advances in prenatal and neonatal care have substantially improved their survival, and the first generations who have benefited from these advances are now entering middle age. While most lead healthy lives, on average these adults are characterised by a number of adversities. These include cardiometabolic risk factors, airway obstruction, less physical activity, poorer visual function, lower cognitive performance, and a behavioural phenotype that includes inattention and internalising and socially withdrawn behaviour that may affect life chances and quality of life. Outcomes in later adulthood are largely unknown, and identifying trajectories of risk or resilience is essential in developing targeted interventions. Joint analyses of data and maintenance of follow-up of cohorts entering adulthood are essential. Such analyses are ongoing within the Adults Born Preterm International Collaboration (APIC; www.apic-preterm.org). Joint analyses require data harmonisation, highlighting the importance of consistent assessment methodologies.

Objective: To present an expert recommendation on Common Core Assessments to be used in follow-up assessments of adults born preterm.

Methods: Principles of Common Core Assessments were discussed at APIC meetings. Experts for each specific outcome domain wrote the first draft on assessments pertaining to that outcome. These drafts were combined and reviewed by all authors. Consensus was reached by discussion at APIC meetings.

Results: We present a recommendation by APIC experts on consistent measures to be used in adult follow-up assessments.

Conclusions: The recommendation encompasses both "core" measures which we recommend to use in all assessments of adults born preterm that include the particular outcome. This will allow comparability between time and location. The recommendation also lists optional measures, focusing on current gaps in knowledge. It includes sections on study design, cardiometabolic and related biomarkers, biological samples, life style, respiratory, ophthalmic, cognitive, mental health, personality, quality of life, sociodemographics, social relationships, and reproduction.
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http://dx.doi.org/10.1111/ppe.12694DOI Listing
May 2021

Genome-wide association study identifies 48 common genetic variants associated with handedness.

Nat Hum Behav 2021 01 28;5(1):59-70. Epub 2020 Sep 28.

Institute of Biological Psychiatry, Mental Health Services of Copenhagen, Copenhagen, Denmark.

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (r = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.
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http://dx.doi.org/10.1038/s41562-020-00956-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116623PMC
January 2021
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