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1.
Eur J Epidemiol ; 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31494793

RESUMO

Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 ± 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUCcrossvalidation 0.925 ± 0.021, AUCexternalvalidation0.914), former (0.766 ± 0.023, 0.699) and never smoking (0.830 ± 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 ± 0.068, 0.796; 15 pack-years 0.767 ± 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 ± 0.024, 0.760; 10 years 0.766 ± 0.033, 0.764; 15 years 0.767 ± 0.020, 0.754). Model application to children revealed highly accurate inference of the true non-smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications.

2.
Behav Genet ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31502010

RESUMO

Bullying comes in different forms, yet most previous genetically-sensitive studies have not distinguished between them. Given the serious consequences and the high prevalence of bullying, it is remarkable that the aetiology of bullying and its different forms has been under-researched. We present the first study to investigate the genetic architecture of bullying perpetration, bullying victimization, and their co-occurrence for verbal, physical and relational bullying. Primary-school teachers rated 8215 twin children on bullying perpetration and bullying victimization. For each form of bullying, we investigated, through genetic structural equation modelling, the genetic and environmental influences on being a bully, a victim or both. 34% of the children were involved as bully, victim, or both. The correlation between being a bully and being a victim varied from 0.59 (relational) to 0.85 (physical). Heritability was ~ 70% for perpetration and ~ 65% for victimization, similar in girls and boys, yet both were somewhat lower for the relational form. Shared environmental influences were modest and more pronounced among girls. The correlation between being a bully and being a victim was explained mostly by genetic factors for verbal (~ 71%) and especially physical (~ 77%) and mostly by environmental factors for relational perpetration and victimization (~ 60%). Genes play a large role in explaining which children are at high risk of being a victim, bully, or both. For victimization this suggests an evocative gene-environment correlation: some children are at risk of being exposed to bullying, partly due to genetically influenced traits. So, genetic influences make some children more vulnerable to become a bully, victim or both.

3.
Transl Psychiatry ; 9(1): 219, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488809

RESUMO

Trials testing the effect of vitamin D or omega-3 polyunsaturated fatty acid (n3-PUFA) supplementation on major depressive disorder (MDD) reported conflicting findings. These trials were inspired by epidemiological evidence suggesting an inverse association of circulating 25-hydroxyvitamin D (25-OH-D) and n3-PUFA levels with MDD. Observational associations may emerge from unresolved confounding, shared genetic risk, or direct causal relationships. We explored the nature of these associations exploiting data and statistical tools from genomics. Results from genome-wide association studies on 25-OH-D (N = 79 366), n3-PUFA (N = 24 925), and MDD (135 458 cases, 344 901 controls) were applied to individual-level data (>2000 subjects with measures of genotype, DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) lifetime MDD diagnoses and circulating 25-OH-D and n3-PUFA) and summary-level data analyses. Shared genetic risk between traits was tested by polygenic risk scores (PRS). Two-sample Mendelian Randomization (2SMR) analyses tested the potential bidirectional causality between traits. In individual-level data analyses, PRS were associated with the phenotype of the same trait (PRS 25-OH-D p = 1.4e - 20, PRS n3-PUFA p = 9.3e - 6, PRS MDD p = 1.4e - 4), but not with the other phenotypes, suggesting a lack of shared genetic effects. In summary-level data analyses, 2SMR analyses provided no evidence of a causal role on MDD of 25-OH-D (p = 0.50) or n3-PUFA (p = 0.16), or for a causal role of MDD on 25-OH-D (p = 0.25) or n3-PUFA (p = 0.66). Applying genomics tools indicated that shared genetic risk or direct causality between 25-OH-D, n3-PUFA, and MDD is unlikely: unresolved confounding may explain the associations reported in observational studies. These findings represent a cautionary tale for testing supplementation of these compounds in preventing or treating MDD.

4.
Child Dev ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31364163

RESUMO

To examine the contributions of maternal and paternal age on offspring externalizing and internalizing problems, this study analyzed problem behaviors at age 10-12 years from four Dutch population-based cohorts (N = 32,892) by a multiple informant design. Bayesian evidence synthesis was used to combine results across cohorts with 50% of the data analyzed for discovery and 50% for confirmation. There was evidence of a robust negative linear relation between parental age and externalizing problems as reported by parents. In teacher-reports, this relation was largely explained by parental socio-economic status. Parental age had limited to no association with internalizing problems. Thus, in this large population-based study, either a beneficial or no effect of advanced parenthood on child problem behavior was observed.

5.
Sci Rep ; 9(1): 11623, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406173

RESUMO

Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10-6), methionine (p-value = 9.2 × 10-5), tyrosine (p-value = 2.1 × 10-4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10-4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10-4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10-4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.

6.
Psychiatr Genet ; 29(5): 170-190, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31464998

RESUMO

There are substantial differences, or variation, between humans in aggression, with its molecular genetic basis mostly unknown. This review summarizes knowledge on the genetic contribution to variation in aggression with the following three foci: (1) a comprehensive overview of reviews on the genetics of human aggression, (2) a systematic review of genome-wide association studies (GWASs), and (3) an automated tool for the selection of literature based on supervised machine learning. The phenotype definition 'aggression' (or 'aggressive behaviour', or 'aggression-related traits') included anger, antisocial behaviour, conduct disorder, and oppositional defiant disorder. The literature search was performed in multiple databases, manually and using a novel automated selection tool, resulting in 18 reviews and 17 GWASs of aggression. Heritability estimates of aggression in children and adults are around 50%, with relatively small fluctuations around this estimate. In 17 GWASs, 817 variants were reported as suggestive (P ≤ 1.0E), including 10 significant associations (P ≤ 5.0E). Nominal associations (P ≤ 1E) were found in gene-based tests for genes involved in immune, endocrine, and nervous systems. Associations were not replicated across GWASs. A complete list of variants and their position in genes and chromosomes are available online. The automated literature search tool produced literature not found by regular search strategies. Aggression in humans is heritable, but its genetic basis remains to be uncovered. No sufficiently large GWASs have been carried out yet. With increases in sample size, we expect aggression to behave like other complex human traits for which GWAS has been successful.

7.
Twin Res Hum Genet ; 22(4): 210-219, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31379313

RESUMO

Twin registries often take part in large collaborative projects and are major contributors to genome-wide association (GWA) meta-analysis studies. In this article, we describe genotyping of twin-family populations from Australia, the Midwestern USA (Avera Twin Register), the Netherlands (Netherlands Twin Register), as well as a sample of mothers of twins from Nigeria to assess the extent, if any, of genetic differences between them. Genotyping in all cohorts was done using a custom-designed Illumina Global Screening Array (GSA), optimized to improve imputation quality for population-specific GWA studies. We investigated the degree of genetic similarity between the populations using several measures of population variation with genotype data generated from the GSA. Visualization of principal component analysis (PCA) revealed that the Australian, Dutch and Midwestern American populations exhibit negligible interpopulation stratification when compared to each other, to a reference European population and to globally distant populations. Estimations of fixation indices (FST values) between the Australian, Midwestern American and Netherlands populations suggest minimal genetic differentiation compared to the estimates between each population and a genetically distinct cohort (i.e., samples from Nigeria genotyped on GSA). Thus, results from this study demonstrate that genotype data from the Australian, Dutch and Midwestern American twin-family populations can be reasonably combined for joint-genetic analysis.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31411322

RESUMO

The prevalence of brain pathologies increases with age and cognitive and physical function worsen over the lifetime. It is unclear whether these processes show a similar increase with age. We studied the association of markers for brain pathology, cognitive and physical function with age in 288 cognitively normal individuals aged 60-102 years selected from the cross-sectional EMIF-AD PreclinAD and 90+ Study at the Amsterdam UMC. An abnormal score was consistent with a score below the 5th percentile in the 60-70 years old individuals. Prevalence of abnormal scores were estimated using generalized estimating equations (GEE) models. The prevalence of abnormal handgrip strength, the Digit Symbol Substitution Test and hippocampal volume showed the fastest increase with age and abnormal MMSE score, muscle mass and amyloid aggregation the lowest. The increase in prevalence of abnormal markers was partly dependent on sex, level of education and amyloid aggregation. We did not find a consistent pattern in which markers of brain pathology and cognitive and physical processes became abnormal with age.

9.
Neuroimage ; 202: 116073, 2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31386921

RESUMO

The human brain is active during rest and hierarchically organized into intrinsic functional networks. These functional networks are largely established early in development, with reports of a shift from a local to more distributed organization during childhood and adolescence. It remains unknown to what extent genetic and environmental influences on functional connectivity change throughout adolescent development. We measured functional connectivity within and between eight cortical networks in a longitudinal resting-state fMRI study of adolescent twins and their older siblings on two occasions (mean ages 13 and 18 years). We modelled the reliability for these inherently noisy and head-motion sensitive measurements by analyzing data from split-half sessions. Functional connectivity between resting-state networks decreased with age whereas functional connectivity within resting-state networks generally increased with age, independent of general cognitive functioning. Sex effects were sparse, with stronger functional connectivity in the default mode network for girls compared to boys, and stronger functional connectivity in the salience network for boys compared to girls. Heritability explained up to 53% of the variation in functional connectivity within and between resting-state networks, and common environment explained up to 33%. Genetic influences on functional connectivity remained stable during adolescent development. In conclusion, longitudinal age-related changes in functional connectivity within and between cortical resting-state networks are subtle but wide-spread throughout adolescence. Genes play a considerable role in explaining individual variation in functional connectivity with mostly stable influences throughout adolescence.

10.
Nicotine Tob Res ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31294817

RESUMO

INTRODUCTION: FTND (FagerstrÓ§m test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. METHODS: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. RESULTS: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. CONCLUSIONS: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. IMPLICATIONS: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

11.
J Innate Immun ; : 1-12, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31230049

RESUMO

The incidence of bacterial infections and sepsis, as well as the mortality risk from sepsis, is sex specific. These clinical findings have been attributed to sex differences in immune responsiveness. The aim of the present study was to investigate sex differences in monocyte-derived cytokine production response upon stimulation with the gram-negative stimulus lipopolysaccharide (LPS) using cytokine data from 15 study populations. Individual data on ex vivo cytokine production response upon stimulation with LPS in whole blood were available for 4,020 subjects originating from these 15 study populations, either from the general population or from patient populations with specific diseases. Men had a stronger cytokine production response than women to LPS for tumour necrosis factor-α, interleukin (IL)-6, IL-12, IL-1ß, IL-1RA, and IL-10, but not for interferon-γ. The granulocyte-macrophage colony-stimulating factor production response was lower in men than in women. These sex differences were independent of chronological age. As men had higher monocyte concentrations, we normalized the cytokine production responses for monocyte concentration. After normalization, the sex differences in cytokine production response to LPS disappeared, except for IL-10, for which the production response was lower in men than in women. A sex-based approach to interpreting immune responsiveness is crucial.

12.
Nat Neurosci ; 22(7): 1196, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31168101

RESUMO

Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.

14.
Twin Res Hum Genet ; 22(3): 164-176, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31198125

RESUMO

A literature review was carried out to identify pre and perinatal characteristics associated with variation in Apgar scores in population-based studies. The parameters identified in the literature search were included in the classical twin design study to estimate effects of pre and perinatal factors shared and nonshared by twins and to test for a contribution of genetic factors in 1- and 5-min Apgar scores in a large sample of Dutch monozygotic (MZ) and dizygotic (DZ) twins. The sample included MZ and DZ twins (N = 5181 pairs) recruited by the Netherlands Twin Register shortly after birth, with data on prenatal characteristics and Apgar scores at first and/or fifth minutes. The ordinal regression and structural equation modeling were used to analyze the effects of characteristics identified in the literature review and to estimate genetic and nongenetic variance components. The literature review identified 63 papers. Consistent with the review, we observed statistically significant effects of birth order, zygosity and gestational age (GA) for 1- and 5-min Apgar scores of both twins. Apgar scores are higher in first-born versus second-born twins and DZ first-born versus MZ first-born twins. Birth weight had an effect on the 5-min Apgar of the first born. Fetal presentation and mode of delivery had different effects on Apgar scores of first- and second-born twins. Parental characteristics and chorionicity did not have significant main effects on Apgar scores. The MZ twins' Apgar correlations equaled the DZ Apgar correlations. Our analyses suggest that individual differences in 1- and 5-min Apgar scores are attributable to shared and nonshared pre and perinatal factors, but not to genotypic factors of the newborns. The main predictors of Apgar scores are birth order, zygosity, GA, birth weight, mode of delivery and fetal presentation.

15.
Br J Ophthalmol ; 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118186

RESUMO

BACKGROUND/AIMS: As a protrusion from the brain, the retina might reflect the status of the brain. Previous studies showed a decrease in vessel density and foveal avascular zone (FAZ) enlargement on optical coherence tomography angiography (OCTA) in individuals suffering from Alzheimer's disease (AD). This study aims to assess whether such changes are already present in preclinical stages of AD, in a population of monozygotic (MZ) twins. METHODS: 124 cognitively healthy individuals (MZ twins, ages 60-93 years) underwent [18F]flutemetamol amyloid positron emission tomography (PET) scanning and OCTA. PET scans were visually rated for cortical amyloid-beta (Aß) positivity. Parametric global cortical non-displaceable binding potential (BP ND) was used as a continuous measure for Aß aggregation. FAZ size and vessel densities for the inner and outer ring of the macular ETDRS grid and in a 3-6 mm ring around the optic nerve head (ONH) were measured.OCTA measures were associated with visual Aß score, BP ND and amyloid load estimated by twin concordance on visual Aß score. Twin correlations were estimated as a measure of maximum heritability of OCTA measures. RESULTS: 13 of 124 participants were Aß+. Aß+ individuals had significantly higher vessel density than Aß- individuals in all regions but did not differ in FAZ size. Twin analyses showed a positive association between and vessel densities in all regions. BP ND tended to be associated with higher vessel density in the inner ring. Twin correlations were moderate/high for all OCTA parameters except vessel density around the ONH, which correlated weakly. CONCLUSION: Retinal vessel density was higher in individuals with preclinical AD.

16.
Acta Ophthalmol ; 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31058465

RESUMO

PURPOSE: There is urgent need for non-invasive diagnostic biomarkers in the preclinical phase of Alzheimer's Disease (AD). Several studies suggest that retinal thickness is reduced in AD. Here, we aim to test the diagnostic value of retinal thickness in preclinical AD, as defined by cognitively normal individuals with amyloid pathology on PET. METHODS: One hundred and sixty five cognitively healthy monozygotic twins aged ≥ 60 were included from the Netherlands Twin Register taking part in the European Medical Information Framework for Alzheimer's Disease PreclinAD study. Participants underwent [18 F] flutemetamol PET that was visually rated for presence or absence of cortical amyloid beta (Aß). Binding potential (BPND ) was calculated as continuous measure for Aß. Spectral Domain OCT was used to asses total and individual inner retinal layer thickness in the macular region (ETDRS circles) as well as peripapillary retinal nerve fibre layer (pRNFL) thickness. Differences between Aß+ and Aß- individuals and associations between BPND and retinal thickness were analyzed. RESULTS: No differences were found in retinal layer thickness in the macula or pRNFL between Aß+ and Aß- individuals. A positive associations between BPND and macular total retinal thickness was observed in the inner ring (p = 0.018), but this was not statistically significant after correction for multiple testing (p = 0.144). Brain/eye parameters had moderate to high intra-twin correlations (p < 0.001) except visual rating score of Aß, which did not correlate (r = 0.21, p = 0.068). CONCLUSION: Variation in retinal thickness likely reflects genetic differences between individuals, but cannot discriminate between healthy and preclinical AD cases, making its use as biomarker in these early stages limited.

17.
Br J Psychiatry ; 215(2): 468-475, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31057126

RESUMO

BACKGROUND: Studies on neighbourhood characteristics and depression show equivocal results.AimsThis large-scale pooled analysis examines whether urbanisation, socioeconomic, physical and social neighbourhood characteristics are associated with the prevalence and severity of depression. METHOD: Cross-sectional design including data are from eight Dutch cohort studies (n = 32 487). Prevalence of depression, either DSM-IV diagnosis of depressive disorder or scoring for moderately severe depression on symptom scales, and continuous depression severity scores were analysed. Neighbourhood characteristics were linked using postal codes and included (a) urbanisation grade, (b) socioeconomic characteristics: socioeconomic status, home value, social security beneficiaries and non-Dutch ancestry, (c) physical characteristics: air pollution, traffic noise and availability of green space and water, and (d) social characteristics: social cohesion and safety. Multilevel regression analyses were adjusted for the individual's age, gender, educational level and income. Cohort-specific estimates were pooled using random-effects analysis. RESULTS: The pooled analysis showed that higher urbanisation grade (odds ratio (OR) = 1.05, 95% CI 1.01-1.10), lower socioeconomic status (OR = 0.90, 95% CI 0.87-0.95), higher number of social security beneficiaries (OR = 1.12, 95% CI 1.06-1.19), higher percentage of non-Dutch residents (OR = 1.08, 95% CI 1.02-1.14), higher levels of air pollution (OR = 1.07, 95% CI 1.01-1.12), less green space (OR = 0.94, 95% CI 0.88-0.99) and less social safety (OR = 0.92, 95% CI 0.88-0.97) were associated with higher prevalence of depression. All four socioeconomic neighbourhood characteristics and social safety were also consistently associated with continuous depression severity scores. CONCLUSIONS: This large-scale pooled analysis across eight Dutch cohort studies shows that urbanisation and various socioeconomic, physical and social neighbourhood characteristics are associated with depression, indicating that a wide range of environmental aspects may relate to poor mental health.Declaration of interestNone.

18.
Neurology ; 92(16): e1899-e1911, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30944236

RESUMO

OBJECTIVE: To identify a plasma metabolomic biomarker signature for migraine. METHODS: Plasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a 1H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses. RESULTS: Decreases in the level of apolipoprotein A1 (ß -0.10; 95% confidence interval [CI] -0.16, -0.05; adjusted p = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (ß -0.10; 95% CI -0.15, -0.05; adjusted p = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (ß -0.24; 95% CI -0.36, -0.12; adjusted p = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status. CONCLUSIONS: Metabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs.

19.
Biol Psychiatry ; 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31003786

RESUMO

BACKGROUND: Previous studies have reported associations between attention-deficit/hyperactivity disorder symptoms and DNA methylation in children. We report the first epigenome-wide association study meta-analysis of adult attention-deficit/hyperactivity disorder symptoms, based on peripheral blood DNA methylation (Infinium HumanMethylation450K array) in three population-based adult cohorts. METHODS: An epigenome-wide association study was performed in the Netherlands Twin Register (N = 2258, mean age 37 years), Dunedin Multidisciplinary Health and Development Study (N = 800, age 38 years), and Environmental Risk Longitudinal Twin Study (N = 1631, age 18 years), and results were combined through meta-analysis (total sample size N = 4689). Region-based analyses accounting for the correlation between nearby methylation sites were also performed. RESULTS: One epigenome-wide significant differentially methylated position was detected in the Dunedin study, but meta-analysis did not detect differentially methylated positions that were robustly associated across cohorts. In region-based analyses, six significant differentially methylation regions (DMRs) were identified in the Netherlands Twin Register, 19 in the Dunedin study, and none in the Environmental Risk Longitudinal Twin Study. Of these DMRs, 92% were associated with methylation quantitative trait loci, and 68% showed moderate to large blood-brain correlations for DNA methylation levels. DMRs included six nonoverlapping DMRs (three in the Netherlands Twin Register, three in the Dunedin study) in the major histocompatibility complex, which were associated with expression of genes in the major histocompatibility complex, including C4A and C4B, previously implicated in schizophrenia. CONCLUSIONS: Our findings point at new candidate loci involved in immune and neuronal functions that await further replication. Our work also illustrates the need for further research to examine to what extent epigenetic associations with psychiatric traits depend on characteristics such as age, comorbidities, exposures, and genetic background.

20.
Obesity (Silver Spring) ; 27(5): 822-829, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30957987

RESUMO

OBJECTIVE: This study examined the prospective, potentially bidirectional association of aggressive behavior with BMI and body composition across childhood in three population-based cohorts. METHODS: Repeated measures of aggression and BMI were available from the Generation R Study between ages 6 and 10 years (N = 3,974), the Netherlands Twin Register (NTR) between ages 7 and 10 years (N = 10,328), and the Swedish Twin Study of Child and Adolescent Development (TCHAD) between ages 9 and 14 years (N = 1,462). In all samples, aggression was assessed with the Child Behavior Checklist. Fat mass and fat-free mass were available in the Generation R Study. Associations were examined with cross-lagged modeling. RESULTS: Aggressive behavior at baseline was associated with higher BMI at follow-up in the Generation R Study (ß = 0.02, 95% CI: 0.00 to 0.04), in NTR (ß = 0.04, 95% CI: 0.02 to 0.06), and in TCHAD (ß = 0.03, 95% CI: -0.02 to 0.07). Aggressive behavior was prospectively associated with higher fat mass (ß = 0.03, 95% CI: 0.01 to 0.05) but not fat-free mass. There was no evidence that BMI or body composition preceded aggressive behavior. CONCLUSIONS: More aggressive behavior was prospectively associated with higher BMI and fat mass. This suggests that aggression contributes to the obesity problem, and future research should study whether these behavioral pathways to childhood obesity are modifiable.

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