Showing papers by "Stockholm County Council published in 2019"
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TL;DR: The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index.
Abstract: Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
517 citations
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TL;DR: It is concluded that future research needs to consider categorical autism, broader autism phenotypes, as well as autistic traits, and examine more homogenous autism variants by subgroup stratification to enhance the understanding of role of environmental factors in the etiology of ASD.
Abstract: Autism spectrum disorder (ASD) is a neurodevelopmental condition of heterogeneous etiology. While it is widely recognized that genetic and environmental factors and their interactions contribute to autism phenotypes, their precise causal mechanisms remain poorly understood. This article reviews our current understanding of environmental risk factors of ASD and their presumed adverse physiological mechanisms. It comprehensively maps the significance of parental age, teratogenic compounds, perinatal risks, medication, smoking and alcohol use, nutrition, vaccination, toxic exposures, as well as the role of extreme psychosocial factors. Further, we consider the role of potential protective factors such as folate and fatty acid intake. Evidence indicates an increased offspring vulnerability to ASD through advanced maternal and paternal age, valproate intake, toxic chemical exposure, maternal diabetes, enhanced steroidogenic activity, immune activation, and possibly altered zinc–copper cycles and treatment with selective serotonin reuptake inhibitors. Epidemiological studies demonstrate no evidence for vaccination posing an autism risk. It is concluded that future research needs to consider categorical autism, broader autism phenotypes, as well as autistic traits, and examine more homogenous autism variants by subgroup stratification. Our understanding of autism etiology could be advanced by research aimed at disentangling the causal and non-causal environmental effects, both founding and moderating, and gene–environment interplay using twin studies, longitudinal and experimental designs. The specificity of many environmental risks for ASD remains unknown and control of multiple confounders has been limited. Further understanding of the critical windows of neurodevelopmental vulnerability and investigating the fit of multiple hit and cumulative risk models are likely promising approaches in enhancing the understanding of role of environmental factors in the etiology of ASD.
259 citations
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Erasmus University Medical Center1, University of Porto2, University of Western Australia3, Stockholm County Council4, Paris Descartes University5, Maastricht University6, French Institute of Health and Medical Research7, National and Kapodistrian University of Athens8, University Medical Center Groningen9, University of Valencia10, University of Southampton11, Liverpool School of Tropical Medicine12, Université de Sherbrooke13, Norwegian Institute of Public Health14, University of Bologna15, University of Crete16, University Hospital Southampton NHS Foundation Trust17, Ludwig Maximilian University of Munich18, Nofer Institute of Occupational Medicine19, University of California20, Harvard University21, University of Illinois at Chicago22, National Institutes of Health23, Wageningen University and Research Centre24, University of Turku25, Helmholtz Centre for Environmental Research - UFZ26, Jagiellonian University Medical College27, Åbo Akademi University28, Harokopio University29, University College Dublin30, University of Calgary31, Boston Children's Hospital32, University of Copenhagen33, University College Cork34, VU University Medical Center35, University of Helsinki36, University of Turin37, Radboud University Nijmegen38, University of Trieste39, University of Bergen40, Slovak Medical University41, Utrecht University42, Pompeu Fabra University43, Bradford Royal Infirmary44, University of Bristol45
TL;DR: In this paper, the separate and combined associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact were assessed.
258 citations
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Erasmus University Medical Center1, Medical University of Warsaw2, University of Valencia3, University of Porto4, Stockholm County Council5, Paris Descartes University6, Sorbonne7, University of Southern California8, Maastricht University9, University of Crete10, French Institute of Health and Medical Research11, National and Kapodistrian University of Athens12, University Medical Center Groningen13, University of Southampton14, Liverpool School of Tropical Medicine15, Norwegian Institute of Public Health16, Karolinska Institutet17, University of Bologna18, University Hospital Southampton NHS Foundation Trust19, Ludwig Maximilian University of Munich20, Nofer Institute of Occupational Medicine21, University of California, Davis22, University of Illinois at Chicago23, University of Western Australia24, National Institutes of Health25, University College Cork26, University of Bristol27, University of Turku28, Helmholtz Centre for Environmental Research - UFZ29, Jagiellonian University Medical College30, Åbo Akademi University31, Harokopio University32, University College Dublin33, University of Calgary34, Public Health Research Institute35, University of Copenhagen36, University of Southern Denmark37, La Trobe University38, Harvard University39, University of Helsinki40, University of Turin41, University of Trieste42, University of Bergen43, Slovak Medical University44, Boston Children's Hospital45, Utrecht University46, Pompeu Fabra University47, Bradford Royal Infirmary48
TL;DR: In this article, the authors conducted an individual participant data meta-analysis of data from 162,129 mothers and children from 37 pregnancy and birth cohort studies from Europe, North-America and Australia, using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal socio-demographic and life style related characteristics.
Abstract: Background:
Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these risks differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact.
Methods and Findings:
We conducted an individual participant data meta-analysis of data from 162,129 mothers and children from 37 pregnancy and birth cohort studies from Europe, North-America and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges with the risks of overweight/obesity in early- (2.0-5.0 years), mid- (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal socio-demographic and life style related characteristics. We observed that a higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (Odds Ratios (OR) for overweight/obesity in early-, mid- and late childhood, respectively: 1.66 (95% Confidence Interval (CI): 1.56, 1.78), OR 1.91 (95% CI: 1.85, 1.98), and OR 2.28 (95% CI: 2.08, 2.50) for maternal overweight, OR 2.43 (95% CI: 2.24, 2.64), OR 3.12 (95% CI: 2.98, 3.27), and OR 4.47 (95% CI: 3.99, 5.23) for maternal obesity, and OR 1.39 (95% CI: 1.30, 1.49), OR 1.55 (95% CI: 1.49, 1.60), and 1.72 (95% CI: 1.56, 1.91) for excessive gestational weight gain. The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity and excessive gestational weight gain ranged from 10.2 to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (P-values for interactions of maternal BMI with gestational weight gain: p=0.038, p<0.001 and p=0.637, in early-, mid- and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North-America and Australia, results need to be interpreted with caution with respect to other populations.
Conclusions:
In this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.
248 citations
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TL;DR: The first in vivo evidence supporting a role for glial activation in FM pathophysiology is provided, and higher subjective ratings of fatigue in FM patients were associated with higher [11C]PBR28 SUVR in the anterior and posterior middle cingulate cortices.
Abstract: Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [11C]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [11C]PBR28 PET. 11 FM patients and 11 HC were scanned using [11C]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (VT) were computed from the [11C]PBR28 data. [11C]-L-deprenyl-D2 was quantified using λ k3. PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [11C]PBR28 VT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [11C]-L-deprenyl-D2 signal, including those demonstrating elevated [11C]PBR28 signal in patients (p's ≥ 0.53, uncorrected). The elevations in [11C]PBR28 VT and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [11C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [11C]PBR28 signal were not also accompanied by increased [11C]-L-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [11C]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.
166 citations
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National Institutes of Health1, University Medical Center Groningen2, Erasmus University Rotterdam3, Pompeu Fabra University4, Karolinska Institutet5, University of Southampton6, Norwegian Institute of Public Health7, Oslo University Hospital8, Curtin University9, University of Western Australia10, University of California, San Francisco11, Anschutz Medical Campus12, University of Bristol13, North Carolina State University14, University of Southern California15, Imperial College London16, Ludwig Maximilian University of Munich17, University of Helsinki18, Université du Québec à Chicoutimi19, Stockholm County Council20, Duke University21, University of Paris22, University of Southern Denmark23, University of Oulu24, University of Memphis25, Helsinki University Central Hospital26, Oulu University Hospital27, Boston Children's Hospital28, King's College London29, Utrecht University30, Max Planck Society31, Emory University32, Karolinska University Hospital33
TL;DR: This article identified differential DNA methylation profiles in newborns and children related to childhood asthma, and identified differentially methylated regions in the newborns' DNA and children's DNA methylations.
Abstract: Background Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. Objective We sought to identify differential DNA methylation in newborns and children related to childhood asthma. Methods Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. Results In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate Conclusion Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.
133 citations
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TL;DR: In this article, a meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium was conducted, and the authors found that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation.
Abstract: Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
128 citations
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TL;DR: Stress related disorders are robustly associated with multiple types of cardiovascular disease, independently of familial background, history of somatic/psychiatric diseases, and psychiatric comorbidity.
Abstract: Objective To assess the association between stress related disorders and subsequent risk of cardiovascular disease. Design Population based, sibling controlled cohort study. Setting Population of Sweden. Participants 136 637 patients in the Swedish National Patient Register with stress related disorders, including post-traumatic stress disorder (PTSD), acute stress reaction, adjustment disorder, and other stress reactions, from 1987 to 2013; 171 314 unaffected full siblings of these patients; and 1 366 370 matched unexposed people from the general population. Main outcome measures Primary diagnosis of incident cardiovascular disease—any or specific subtypes (ischaemic heart disease, cerebrovascular disease, emboli/thrombosis, hypertensive diseases, heart failure, arrhythmia/conduction disorder, and fatal cardiovascular disease)—and 16 individual diagnoses of cardiovascular disease. Hazard ratios for cardiovascular disease were derived from Cox models, after controlling for multiple confounders. Results During up to 27 years of follow-up, the crude incidence rate of any cardiovascular disease was 10.5, 8.4, and 6.9 per 1000 person years among exposed patients, their unaffected full siblings, and the matched unexposed individuals, respectively. In sibling based comparisons, the hazard ratio for any cardiovascular disease was 1.64 (95% confidence interval 1.45 to 1.84), with the highest subtype specific hazard ratio observed for heart failure (6.95, 1.88 to 25.68), during the first year after the diagnosis of any stress related disorder. Beyond one year, the hazard ratios became lower (overall 1.29, 1.24 to 1.34), ranging from 1.12 (1.04 to 1.21) for arrhythmia to 2.02 (1.45 to 2.82) for artery thrombosis/embolus. Stress related disorders were more strongly associated with early onset cardiovascular diseases (hazard ratio 1.40 (1.32 to 1.49) for attained age Conclusion Stress related disorders are robustly associated with multiple types of cardiovascular disease, independently of familial background, history of somatic/psychiatric diseases, and psychiatric comorbidity.
120 citations
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TL;DR: This cohort study examines whether maternal anemia during pregnancy is associated with risk of autism spectrum disorder, attention-deficit/hyperactivity disorder, and intellectual disability in youths.
Abstract: Importance Given the critical role that iron plays in neurodevelopment, an association between prenatal iron deficiency and later risk of neurodevelopmental disorders, such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID), is plausible. Objective To test the a priori hypothesis that anemia diagnosed in mothers during pregnancy is associated with an increased risk of ASD, ADHD, and ID in offspring and that the magnitude of the risk varies with regard to the timing of anemia in pregnancy. Design, Setting, and Participants This cohort study used health and population register data from the Stockholm Youth Cohort to evaluate 532 232 nonadoptive children born from January 1, 1987, to December 31, 2010, in Sweden, with follow-up in health registers until December 31, 2016. Data analysis was performed from January 15, 2018, to June 20, 2018. Exposures Registered diagnoses of anemia during pregnancy. Gestational timing of the first recorded anemia diagnosis (≤30 weeks or >30 weeks) was considered to assess potential critical windows of development. Main Outcomes and Measures Registered diagnoses of ASD, ADHD, or ID or co-occurring combinations of these disorders. Results The cohort included 532 232 individuals (272 884 [51.3%] male) between 6 and 29 years of age at the end of follow-up (mean [SD] age, 17.6 [7.1] years) and their 299 768 mothers. The prevalence of ASD, ADHD, and ID was higher among children born to mothers diagnosed with anemia within the first 30 weeks of pregnancy (4.9% ASD, 9.3% ADHD, and 3.1% ID) compared with mothers with anemia diagnosed later in pregnancy (3.8% ASD, 7.2% ADHD, and 1.1% ID) or mothers not diagnosed with anemia (3.5% ASD, 7.1% ADHD, and 1.3% ID). Anemia diagnosed during the first 30 weeks of pregnancy but not later was associated with increased risk of diagnosis of ASD (odds ratio [OR], 1.44; 95% CI, 1.13-1.84), ADHD (OR, 1.37; 95% CI, 1.14-1.64), and ID (OR, 2.20; 95% CI, 1.61-3.01) in offspring in models that included socioeconomic, maternal, and pregnancy-related factors. Early anemia diagnosis was similarly associated with risk of ASD (OR, 2.25; 95% CI, 1.24-4.11) and ID (OR, 2.59; 95% CI, 1.08-6.22) in a matched sibling comparison. Considering mutually exclusive diagnostic groups, we observed the strongest association between anemia and ID without co-occurring ASD (OR, 2.72; 95% CI, 1.84-4.01). Associations of these disorders with anemia diagnosed later in pregnancy were greatly diminished. Conclusions and Relevance In contrast to maternal anemia diagnosed toward the end of pregnancy, anemia diagnosed earlier in pregnancy was associated with increased risk of the development of ASD, ADHD, and particularly ID in offspring. Given that iron deficiency and anemia are common among women of childbearing age, our findings emphasize the importance of early screening for iron status and nutritional counseling in antenatal care.
117 citations
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TL;DR: Improvements in a range of molecular, histopathological, electrophysiological and functional endpoints are demonstrated and support the continued development of an allele-selective ZFP-TF for the treatment of Huntington’s disease.
Abstract: Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin gene (HTT), which codes for the pathologic mutant HTT (mHTT) protein. Since normal HTT is thought to be important for brain function, we engineered zinc finger protein transcription factors (ZFP-TFs) to target the pathogenic CAG repeat and selectively lower mHTT as a therapeutic strategy. Using patient-derived fibroblasts and neurons, we demonstrate that ZFP-TFs selectively repress >99% of HD-causing alleles over a wide dose range while preserving expression of >86% of normal alleles. Other CAG-containing genes are minimally affected, and virally delivered ZFP-TFs are active and well tolerated in HD neurons beyond 100 days in culture and for at least nine months in the mouse brain. Using three HD mouse models, we demonstrate improvements in a range of molecular, histopathological, electrophysiological and functional endpoints. Our findings support the continued development of an allele-selective ZFP-TF for the treatment of HD. Zinc finger protein transcription factors are developed for the selective silencing of the mutant huntingtin gene in human neurons in vitro and multiple animal models of Huntington’s disease in vivo while preserving expression of the wild-type allele.
115 citations
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02 Aug 2019
TL;DR: This systematic review and meta-analysis examines the association between birth by cesarean delivery and risk of neurodevelopmental and psychiatric disorders in the offspring compared with birth by vaginal delivery.
Abstract: Importance Birth by cesarean delivery is increasing globally, particularly cesarean deliveries without medical indication. Children born via cesarean delivery may have an increased risk of negative health outcomes, but the evidence for psychiatric disorders is incomplete. Objective To evaluate the association between cesarean delivery and risk of neurodevelopmental and psychiatric disorders in the offspring. Data Sources Ovid MEDLINE, Embase, Web of Science, and PsycINFO were searched from inception to December 19, 2018. Search terms included all main mental disorders in theDiagnostic and Statistical Manual of Mental Disorders(Fifth Edition). Study Selection Two researchers independently selected observational studies that examined the association between cesarean delivery and neurodevelopmental and psychiatric disorders in the offspring. Data Extraction and Synthesis Two researchers independently extracted data according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines and assessed study quality using the Newcastle-Ottawa Scale. Random-effects meta-analyses were used to pool odds ratios (ORs) with 95% CIs for each outcome. Sensitivity and influence analyses tested the robustness of the results. Main Outcomes and Measures The ORs for the offspring with any neurodevelopmental or psychiatric disorder who were born via cesarean delivery compared with those were born via vaginal delivery. Results A total of 6953 articles were identified, of which 61 studies comprising 67 independent samples were included, totaling 20 607 935 deliveries. Compared with offspring born by vaginal delivery, offspring born via cesarean delivery had increased odds of autism spectrum disorders (OR, 1.33; 95% CI, 1.25-1.41;I2 = 69.5%) and attention-deficit/hyperactivity disorder (OR, 1.17; 95% CI, 1.07-1.26;I2 = 79.2%). Estimates were less precise for intellectual disabilities (OR, 1.83; 95% CI, 0.90-3.70;I2 = 88.2%), obsessive-compulsive disorder (OR, 1.49; 95% CI, 0.87-2.56;I2 = 67.3%), tic disorders (OR, 1.31; 95% CI, 0.98-1.76;I2 = 75.6%), and eating disorders (OR, 1.18; 95% CI, 0.96-1.47;I2 = 92.7%). No significant associations were found with depression/affective psychoses or nonaffective psychoses. Estimates were comparable for emergency and elective cesarean delivery. Study quality was high for 82% of the cohort studies and 50% of the case-control studies. Conclusions and Relevance The findings suggest that cesarean delivery births are associated with an increased risk of autism spectrum disorder and attention-deficit/hyperactivity disorder, irrespective of cesarean delivery modality, compared with vaginal delivery. Future studies on the mechanisms behind these associations appear to be warranted.
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TL;DR: It is shown for the first time that low-cost, off-the-shelf consumer VR hardware and software can be used to conduct exposure therapy for PSA, both in the traditional, previously impractical one-session format, and in a novel self-led, at-home format.
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TL;DR: A new method and tools for using summary statistics from previously published test-retest studies to approximate the reliability of outcomes in new samples will allow researchers to avoid performing costly studies which are, by virtue of their design, unlikely to yield informative conclusions.
Abstract: Neuroimaging, in addition to many other fields of clinical research, is both time-consuming and expensive, and recruitable patients can be scarce. These constraints limit the possibility of large-sample experimental designs, and often lead to statistically underpowered studies. This problem is exacerbated by the use of outcome measures whose accuracy is sometimes insufficient to answer the scientific questions posed. Reliability is usually assessed in validation studies using healthy participants, however these results are often not easily applicable to clinical studies examining different populations. I present a new method and tools for using summary statistics from previously published test-retest studies to approximate the reliability of outcomes in new samples. In this way, the feasibility of a new study can be assessed during planning stages, and before collecting any new data. An R package called relfeas also accompanies this article for performing these calculations. In summary, these methods and tools will allow researchers to avoid performing costly studies which are, by virtue of their design, unlikely to yield informative conclusions.
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TL;DR: The presence of ANO2 reactivity associates with a high MS risk, in particular together with HLA risk variants and high EBNA1 antibody titers, which is considered a strong argument for its relevance in MS ethiopathogenesis.
Abstract: Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr vir ...
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TL;DR: A comprehensively characterize ASD-related alterations within and between 20 well-characterized resting-state networks using baseline data from the EU-AIMS (European Autism Interventions-A Multicentre Study for Developing New Medications) Longitudinal European Autism Project and investigates case-control differences and autism trait- related alterations in between-network connectivity.
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TL;DR: Overall, few consistent associations were observed between the different air pollution measures and IHD or stroke incidence, however, long-term residential exposure to locally emitted BC from traffic exhaust was associated with stroke incidence.
Abstract: BACKGROUND: Long-term exposure to particulate matter (PM) in ambient air has been associated with cardiovascular mortality, but few studies have considered incident disease in relation to PM from d ...
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University of the Balearic Islands1, University of Barcelona2, Stockholm County Council3, Autonomous University of Barcelona4, King's College London5, Pompeu Fabra University6, Carlos III Health Institute7, Icahn School of Medicine at Mount Sinai8, South London and Maudsley NHS Foundation Trust9, Stanford University10, University of California, San Diego11
TL;DR: An umbrella review of systematic reviews and meta-analyses of risk/protective factors for PTSD assessed and graded the evidence of the association between each factor and PTSD and found 57 showed a significant association with PTSD.
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TL;DR: The Autism spectrum disorder Core Sets mark a milestone toward the standardized assessment of autism spectrum disorder–related functioning in educational, administrative, clinical, and research settings.
Abstract: Autism spectrum disorder is associated with diverse social, educational, and occupational challenges. To date, no standardized, internationally accepted tools exist to assess autism spectrum disord ...
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TL;DR: The interactions between EDs and autoimmune diseases support the previously reported associations and the bidirectional risk pattern observed in women suggests either a shared mechanism or a third mediating variable contributing to the association of these illnesses.
Abstract: Background: Immune system dysfunction may be associated with eating disorders, and associations could have implications for detection, risk assessment, and treatment of both autoimmune diseases and eating disorders. However, questions regarding the nature of the relationship between these two disease entities remain. We evaluated the strength of associations for the bidirectional relationships between eating disorders and autoimmune diseases.
Methods: In this nationwide population-based cohort study, Swedish registers were linked to establish a cohort of more than 2.5 million individuals born in Sweden between January 1, 1979 and December 31, 2005 and followed-up until December 2013. Cox proportional hazard regression models were used to investigate: 1) subsequent risk of eating disorders in individuals with autoimmune diseases; and 2) subsequent risk of autoimmune diseases in individuals with eating disorders.
Results: We observed a strong, bidirectional relationship between the two classes of illness indicating that diagnosis in one illness class increased the risk of the other. In women, autoimmune disease diagnoses increased subsequent hazard of anorexia nervosa, bulimia nervosa, and other eating disorders. Similarly, anorexia nervosa, bulimia nervosa, and other eating disorders increased subsequent hazard of autoimmune diseases. The gastrointestinal-related autoimmune diseases celiac disease and Crohn's disease showed a bidirectional relationship with anorexia nervosa and other eating disorders. Psoriasis showed a bidirectional relationship with other eating disorders. Prior type 1 diabetes increased risk for anorexia nervosa, bulimia nervosa, and other eating disorders. In men, we did not observe a bidirectional pattern, but prior autoimmune arthritis increased risk for other eating disorders.
Conclusions: The associations between eating disorders and autoimmune diseases provide additional support for previously reported associations. The bidirectional risk pattern observed in women suggests either a shared mechanism or a third mediating variable contributing to the association of these illnesses.
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TL;DR: In this article, the authors show that individuals with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for poor school performance, and pharmacological treatment of ADHD may have beneficial effects on s...
Abstract: OBJECTIVE: Individuals with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for poor school performance, and pharmacological treatment of ADHD may have beneficial effects on s ...
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TL;DR: It is shown for the first time that sensory symptoms, repetitive behavior and associated psychiatric symptoms do not independently contribute to adaptive function impairments that people with ASD experience.
Abstract: Individuals with autism spectrum disorder (ASD) exhibit significant impairments in adaptive functioning that impact on their ability to meet the demands of everyday life. A recurrent finding is that there is a pronounced discrepancy between level of cognitive ability and adaptive functioning, and this is particularly prominent among higher-ability individuals. However, the key clinical and demographic associations of these discrepancies remain unclear. This study included a sample of 417 children, adolescents, and adults with ASD as part of the EU-AIMS LEAP cohort. We examined how age, sex, IQ, levels of ASD symptom and autistic trait severity and psychiatric symptomatology are associated with adaptive functioning as measured by the Vineland Adaptive Behavior Scales-Second Edition and IQ-adaptive functioning discrepancies. Older age, lower IQ and higher social-communication symptoms were associated with lower adaptive functioning. Results also demonstrate that older age, higher IQ and higher social-communication symptoms are associated with greater IQ-adaptive functioning discrepancy scores. By contrast, sensory ASD symptoms, repetitive and restricted behaviors, as well as symptoms of attention deficit/hyperactivity disorder (ADHD), anxiety and depression, were not associated with adaptive functioning or IQ-adaptive functioning discrepancy scores. These findings suggest that it is the core social communication problems that define ASD that contribute to adaptive function impairments that people with ASD experience. They show for the first time that sensory symptoms, repetitive behavior and associated psychiatric symptoms do not independently contribute to adaptive function impairments. Individuals with ASD require supportive interventions across the lifespan that take account of social-communicative ASD symptom severity. Autism Res 2019, 12: 645-657. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: This study investigated key clinical and demographic associations of adaptive functioning impairments in individuals with autism. We found that older age, lower IQ and more severe social-communicative symptoms, but not sensory or repetitive symptoms or co-occurring psychiatric symptoms, are associated with lower adaptive functioning and greater ability-adaptive function discrepancies. This suggests that interventions targeting adaptive skills acquisition should be flexible in their timing and intensity across developmental periods, levels of cognitive ability and take account of social-communicative ASD symptom severity.
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Cardiff University1, VU University Amsterdam2, Oslo University Hospital3, Stockholm County Council4, Trinity College, Dublin5, National University of Ireland, Galway6, University of Bonn7, University of Palermo8, King's College London9, Martin Luther University of Halle-Wittenberg10, Utrecht University11, Erasmus University Rotterdam12, Semel Institute for Neuroscience and Human Behavior13, South London and Maudsley NHS Foundation Trust14, University of California, Los Angeles15, University Medical Center Utrecht16, Maastricht University17, Harvard University18, Broad Institute19, Heidelberg University20, Maastricht University Medical Centre21, University of North Carolina at Chapel Hill22, University Hospital Bonn23, German Center for Neurodegenerative Diseases24
TL;DR: Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders, suggesting the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself.
Abstract: Background Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. Methods We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. Results PRS for both population IQ (P = 4.39 × 10–28) and EA (P = 1.27 × 10–26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. Conclusions Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.
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TL;DR: Certain factors, smoking, EBV infection, and obesity interact with human leukocyte antigen (HLA) risk genes, arguing for a pathogenic pathway involving adaptive immunity.
Abstract: Lifestyle and environmental factors potently influence the risk of multiple sclerosis (MS), because genetic predisposition only explains a fraction of the risk increase. There is strong evidence for associations of Epstein-Barr virus (EBV) infection, smoking, sun exposure/vitamin D, and adolescent obesity to risk of MS. There is also circumstantial evidence on organic solvents and shift work, all associate with greater risk, although certain factors like nicotine, alcohol, and a high coffee consumption associate with a reduced risk. Certain factors, smoking, EBV infection, and obesity interact with human leukocyte antigen (HLA) risk genes, arguing for a pathogenic pathway involving adaptive immunity. There is a potential for prevention, in particular for people at greater risk such as relatives of individuals with MS. All of the described factors for MS may influence adaptive and/or innate immunity, as has been argued for MS risk gene variants.
Erasmus University Medical Center1, Medical University of Warsaw2, University of Valencia3, University of Porto4, Stockholm County Council5, Paris Descartes University6, Sorbonne7, University of Crete8, Maastricht University9, University of Southern California10, French Institute of Health and Medical Research11, National and Kapodistrian University of Athens12, University Medical Center Groningen13, University of Southampton14, Liverpool School of Tropical Medicine15, Norwegian Institute of Public Health16, Karolinska Institutet17, University of Bologna18, University Hospital Southampton NHS Foundation Trust19, Ludwig Maximilian University of Munich20, Nofer Institute of Occupational Medicine21, University of California, Davis22, University of Illinois at Chicago23, University of Western Australia24, National Institutes of Health25, University College Cork26, University of Bristol27, University of Turku28, Helmholtz Centre for Environmental Research - UFZ29, Jagiellonian University Medical College30, Åbo Akademi University31, Harokopio University32, University College Dublin33, University of Calgary34, Public Health Research Institute35, University of Copenhagen36, University of Southern Denmark37, La Trobe University38, Harvard University39, University of Helsinki40, University of Turin41, University of Trieste42, University of Bergen43, Slovak Medical University44, Boston Children's Hospital45, Utrecht University46, Pompeu Fabra University47, Bradford Royal Infirmary48
TL;DR: Higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages, and future intervention trials should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.
Abstract: Background:
Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these risks differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact.
Methods and Findings:
We conducted an individual participant data meta-analysis of data from 162,129 mothers and children from 37 pregnancy and birth cohort studies from Europe, North-America and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges with the risks of overweight/obesity in early- (2.0-5.0 years), mid- (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal socio-demographic and life style related characteristics. We observed that a higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (Odds Ratios (OR) for overweight/obesity in early-, mid- and late childhood, respectively: 1.66 (95% Confidence Interval (CI): 1.56, 1.78), OR 1.91 (95% CI: 1.85, 1.98), and OR 2.28 (95% CI: 2.08, 2.50) for maternal overweight, OR 2.43 (95% CI: 2.24, 2.64), OR 3.12 (95% CI: 2.98, 3.27), and OR 4.47 (95% CI: 3.99, 5.23) for maternal obesity, and OR 1.39 (95% CI: 1.30, 1.49), OR 1.55 (95% CI: 1.49, 1.60), and 1.72 (95% CI: 1.56, 1.91) for excessive gestational weight gain. The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity and excessive gestational weight gain ranged from 10.2 to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (P-values for interactions of maternal BMI with gestational weight gain: p=0.038, p<0.001 and p=0.637, in early-, mid- and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North-America and Australia, results need to be interpreted with caution with respect to other populations.
Conclusions:
In this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.
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Radboud University Nijmegen1, Utrecht University2, Harvard University3, Broad Institute4, Aarhus University5, Lundbeck6, University of North Carolina at Chapel Hill7, University of Southern California8, Erasmus University Rotterdam9, University of Toronto10, King's College London11, University of Würzburg12, Karolinska Institutet13, Stockholm County Council14, QIMR Berghofer Medical Research Institute15, State University of New York Upstate Medical University16, University of Bergen17
TL;DR: This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level.
Abstract: Objective:Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the n...
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TL;DR: It is suggested that during an important period for the development of social cognition (10-18 months of age), infants later diagnosed with ASD show marked atypicalities in IJA but not in RJA, which indicates that IJA is an important target for future prodromal intervention trials.
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TL;DR: The majority of RA patients had moderate/severe periodontitis and that this severe form of the disease was significantly associated with ACPA positivity, an altered subgingival microbial profile, and increased levels of systemic and oral inflammatory mediators.
Abstract: This study aimed to investigate the periodontal health of patients with established rheumatoid arthritis (RA) in relation to oral microbiota, systemic and oral inflammatory mediators, and RA disease activity. Forty patients underwent full-mouth dental/periodontal and rheumatological examination, including collection of blood, saliva, gingival crevicular fluid (GCF) and subgingival plaque. Composition of plaque and saliva microbiota were analysed using 16S rRNA sequencing and levels of inflammatory mediators by multiplex-immunoassay. The majority of the patients (75%) had moderate or severe periodontitis and the rest had no/mild periodontitis. Anti-citrullinated protein antibody (ACPA) positivity was significantly more frequent in the moderate/severe periodontitis (86%) compared to the no/mild group (50%). No significance between groups was observed for RA disease duration or activity, or type of medication. Levels of sCD30/TNFRSF8, IFN-α2, IL-19, IL-26, MMP-1, gp130/sIL-6Rs, and sTNF-R1 were significantly higher in serum or GCF, and April/TNFSF13 was significantly higher in serum and saliva samples in moderate/severe periodontitis. The microbial composition in plaque also differed significantly between the two groups. In conclusion, the majority of RA patients had moderate/severe periodontitis and that this severe form of the disease was significantly associated with ACPA positivity, an altered subgingival microbial profile, and increased levels of systemic and oral inflammatory mediators.
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TL;DR: An updated statistical methodology for heritability estimation in BPD is used by taking available time of follow-up into account while controlling for co-variates, demonstrating a robust 60% heritability for BPD with no evidence of sex-specific genetic effects on disease liability.
Abstract: Twin- and family studies have shown variations in the heritability estimates of bipolar disorder (BPD). The current study uses an updated statistical methodology for heritability estimation in BPD by taking available time of follow-up into account while controlling for co-variates. We identified monozygotic and dizygotic same and different sex twins with BPD ( n = 804) or unaffected from BPD ( n = 91,604) from the Swedish Twin Register and the National Patient Register. We applied structural equational modeling with inversed probability weighting to estimate the heritability, taking into account censoring and truncation of data. Sex-limitation models were constructed to analyze qualitative or quantitative sex-differences in BPD. Heritability for BPD was 60.4% (95% Confidence Interval: 50.3–70.5) after age, sex, left-hand truncation and censoring of the data was taken into account. A larger proportion of females were affected from BPD (females 62.2%; males 37.8%, p
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TL;DR: In this paper, the authors investigate trust in the organisation as a potential mechanism that may explain why job insecurity relates to two well-documented outcomes: decreased job satisfaction and lowered mental health.
Abstract: Job insecurity has well-documented negative effects for individuals as well as organisations. However, the mechanisms by which job insecurity relates to its outcomes have received less research attention. The purpose of this study is to investigate trust in the organisation as a potential mechanism that may explain why job insecurity relates to two well-documented outcomes: decreased job satisfaction and lowered mental health. These hypotheses were tested in a Swedish longitudinal sample that consists of employees (longitudinal n = 906) from three organisations, using structural equation modelling. Overall, the results showed support for our hypotheses. Our findings reveal an indirect effect of trust on job satisfaction, regardless of whether the previous levels of job satisfaction were controlled for. With regard to mental health, the indirect effect was only evident when previous levels of mental health were not controlled for. The results of this study contribute to our understanding about the ...
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TL;DR: Low AMR rates were detected against the first-line antibiotics recommended in national UTI treatment guidelines, giving support to their future use and supporting the European Association of Urology guidelines stating that nitrofurantoin, fosfomycin and mecillinam are viable treatment options for uncomplicated UTI.
Abstract: Objectives In the Northern Dimension Antibiotic Resistance Study (NoDARS), Finland, Germany, Latvia, Poland, Russia and Sweden collected urine samples from outpatient women (aged 18–65 years) with symptoms of uncomplicated urinary tract infection (UTI) to investigate the levels of antimicrobial resistance (AMR) among Escherichia coli isolates. Methods A total of 775 E. coli isolates from 1280 clinical urine samples were collected from October 2015 to January 2017. Antimicrobial susceptibility testing was performed and the results were interpreted according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. Results Overall AMR rates to the commonly used antibiotics nitrofurantoin, fosfomycin and mecillinam (except for Germany that was missing a result for mecillinam) were 1.2%, 1.3% and 4.1%, respectively. The highest overall resistance rates were determined for ampicillin (39.6%), trimethoprim (23.8%), trimethoprim/sulfamethoxazole (22.4%), amoxicillin/clavulanic acid (16.7%) and ciprofloxacin (15.1%), varying significantly between countries. The rate of extended-spectrum β-lactamase (ESBL) production was 8.7%. None of the isolates showed resistance to meropenem. Conclusions In most cases, low AMR rates were detected against the first-line antibiotics recommended in national UTI treatment guidelines, giving support to their future use. These results also support the European Association of Urology guidelines stating that nitrofurantoin, fosfomycin and mecillinam are viable treatment options for uncomplicated UTI.