Inconsistent associations between long-term exposure to particles with an aerodynamic diameter
fine particulate matter (
) components and mortality have been reported, partly related to challenges in ...exposure assessment.
We investigated the associations between long-term exposure to
elemental components and mortality in a large pooled European cohort; to compare health effects of
components estimated with two exposure modeling approaches, namely, supervised linear regression (SLR) and random forest (RF) algorithms.
We pooled data from eight European cohorts with 323,782 participants, average age 49 y at baseline (1985-2005). Residential exposure to 2010 annual average concentration of eight
components copper (Cu), iron (Fe), potassium (K), nickel (Ni), sulfur (S), silicon (Si), vanadium (V), and zinc (Zn) was estimated with Europe-wide SLR and RF models at a
scale. We applied Cox proportional hazards models to investigate the associations between components and natural and cause-specific mortality. In addition, two-pollutant analyses were conducted by adjusting each component for
mass and nitrogen dioxide (
) separately.
We observed 46,640 natural-cause deaths with 6,317,235 person-years and an average follow-up of 19.5 y. All SLR-modeled components were statistically significantly associated with natural-cause mortality in single-pollutant models with hazard ratios (HRs) from 1.05 to 1.27. Similar HRs were observed for RF-modeled Cu, Fe, K, S, V, and Zn with wider confidence intervals (CIs). HRs for SLR-modeled Ni, S, Si, V, and Zn remained above unity and (almost) significant after adjustment for both
and
. HRs only remained (almost) significant for RF-modeled K and V in two-pollutant models. The HRs for V were 1.03 (95% CI: 1.02, 1.05) and 1.06 (95% CI: 1.02, 1.10) for SLR- and RF-modeled exposures, respectively, per
, adjusting for
mass. Associations with cause-specific mortality were less consistent in two-pollutant models.
Long-term exposure to V in
was most consistently associated with increased mortality. Associations for the other components were weaker for exposure modeled with RF than SLR in two-pollutant models. https://doi.org/10.1289/EHP8368.
Almost 100% individuals with coeliac disease (CD) are carriers of the human leucocyte antigen (HLA) DQ2/DQ8 alleles. Earlier studies have, however, failed to consider the HLA system when estimating ...heritability in CD, thus violating an underlying assumption of heritability analysis. We examined the heritability of CD in a large population-based sample of twins, considering HLA.
In a population-representative sample of 107 912 twins, we identified individuals with CD (equal to villous atrophy) through biopsy reports from all Swedish pathology departments. We calculated concordance rates and tetrachoric correlations for monozygotic (MZ) and dizygotic (DZ) twin pairs. Further, we estimated heritability of CD, first strictly from observed data, and then the non-HLA heritability, representing the heritability of all genetic factors except the HLA locus, using an approach that circumvent the violation of underlying assumptions.
We identified 513 twins with a diagnosis of CD (prevalence 0.48%). Concordance rates were higher in MZ pairs (0.49) than in DZ pairs (0.10), as were tetrachoric correlations (0.89 in MZ vs 0.51 in DZ pairs). The heritability of CD was 75% (95% CI 55% to 96%). The non-HLA heritability was slightly attenuated, 68% (95% CI 40% to 96%), with shared (17%) and non-shared (15%) environmental factors explaining the remaining variability of CD.
CD is characterised by a high heritability, but our study also suggests that non-shared environmental factors may be of importance to CD development. HLA seems to have only moderate impact on heritability estimates.
The authors sought to determine the risk of treatment-emergent mania associated with methylphenidate, used in monotherapy or with a concomitant mood-stabilizing medication, in patients with bipolar ...disorder.
Using linked Swedish national registries, the authors identified 2,307 adults with bipolar disorder who initiated therapy with methylphenidate between 2006 and 2014. The cohort was divided into two groups: those with and those without concomitant mood-stabilizing treatment. To adjust for individual-specific confounders, including disorder severity, genetic makeup, and early environmental factors, Cox regression analyses were used, conditioning on individual to compare the rate of mania (defined as hospitalization for mania or a new dispensation of stabilizing medication) 0-3 months and 3-6 months after medication start following nontreated periods.
Patients on methylphenidate monotherapy displayed an increased rate of manic episodes within 3 months of medication initiation (hazard ratio=6.7, 95% CI=2.0-22.4), with similar results for the subsequent 3 months. By contrast, for patients taking mood stabilizers, the risk of mania was lower after starting methylphenidate (hazard ratio=0.6, 95% CI=0.4-0.9). Comparable results were observed when only hospitalizations for mania were counted.
No evidence was found for a positive association between methylphenidate and treatment-emergent mania among patients with bipolar disorder who were concomitantly receiving a mood-stabilizing medication. This is clinically important given that up to 20% of people with bipolar disorder suffer from comorbid ADHD. Given the markedly increased hazard ratio of mania following methylphenidate initiation in bipolar patients not taking mood stabilizers, careful assessment to rule out bipolar disorder is indicated before initiating monotherapy with psychostimulants.
Twin studies of hoarding symptoms indicate low to moderate heritability during adolescence and considerably higher heritability in older samples, suggesting dynamic developmental etiological effects. ...The aim of the current study was to estimate the relative contribution of additive genetic and environmental effects to hoarding symptoms during adolescence and young adulthood and to estimate the sources of stability and change of hoarding symptoms during adolescence.
Univariate model-fitting was conducted in three cohorts of twins aged 15 (n = 7,905), 18 (n = 2,495) and 20-28 (n = 6,218). Longitudinal analyses were conducted in a subsample of twins for which data on hoarding symptoms was available at both age 15 and 18 (n = 1,701).
Heritability estimates for hoarding symptoms at ages 15, 18 and 20-28 were 41% (95% confidence interval CI: 36-45%), 31% (95% CI: 22-39%) and 29% (95% CI: 24-34%) respectively. Quantitative sex-differences emerged in twins aged 15 at which point the heritability in boys was 33% (95% CI: 22-41%) and 17% (95% CI: 0-36%) in girls. Shared environmental effects played a negligible role across all samples with the exception of girls aged 15 where they accounted for a significant proportion of the variance (22%; 95% CI 6-36%). The longitudinal bivariate analyses revealed a significant phenotypic correlation of hoarding symptoms between ages 15 and 18 (0.40; 95% CI: 0.36-0.44) and a strong but imperfect genetic correlation (0.75; 95% CI: 0.57-0.94). The bivariate heritability was estimated to 65% (95% CI: 50-79%).
Hoarding symptoms are heritable from adolescence throughout young adulthood, although heritability appears to slightly decrease over time. Shared environmental effects contribute to hoarding symptoms only in girls at age 15. The stability of hoarding symptoms between ages 15 and 18 is largely explained by genetic factors, while non-shared environmental factors primarily have a time-specific effect. The findings indicate that dynamic developmental etiological effects may be operating across the life span.
Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease ...proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.
Dogs may be beneficial in reducing cardiovascular risk in their owners by providing social support and motivation for physical activity. We aimed to investigate the association of dog ownership with ...incident cardiovascular disease (CVD) and death in a register-based prospective nation-wide cohort (n = 3,432,153) with up to 12 years of follow-up. Self-reported health and lifestyle habits were available for 34,202 participants in the Swedish Twin Register. Time-to-event analyses with time-updated covariates were used to calculate hazard ratios (HR) with 95% confidence intervals (CI). In single- and multiple-person households, dog ownership (13.1%) was associated with lower risk of death, HR 0.67 (95% CI, 0.65-0.69) and 0.89 (0.87-0.91), respectively; and CVD death, HR 0.64 (0.59-0.70), and 0.85 (0.81-0.90), respectively. In single-person households, dog ownership was inversely associated with cardiovascular outcomes (HR composite CVD 0.92, 95% CI, 0.89-0.94). Ownership of hunting breed dogs was associated with lowest risk of CVD. Further analysis in the Twin Register could not replicate the reduced risk of CVD or death but also gave no indication of confounding by disability, comorbidities or lifestyle factors. In conclusion, dog ownership appears to be associated with lower risk of CVD in single-person households and lower mortality in the general population.
Epigenetic studies present unique opportunities to advance schizophrenia research because they can potentially account for many of its clinical features and suggest novel strategies to improve ...disease management.
To identify schizophrenia DNA methylation biomarkers in blood.
The sample consisted of 759 schizophrenia cases and 738 controls (N = 1497) collected in Sweden. We used methyl-CpG-binding domain protein-enriched genome sequencing of the methylated genomic fraction, followed by next-generation DNA sequencing. We obtained a mean (SD) number of 68 (26.8) million reads per sample. This massive data set was processed using a specifically designed data analysis pipeline. Critical top findings from our methylome-wide association study (MWAS) were replicated in independent case-control participants using targeted pyrosequencing of bisulfite-converted DNA.
Status of schizophrenia cases and controls.
Our MWAS suggested a considerable number of effects, with 25 sites passing the highly conservative Bonferroni correction and 139 sites significant at a false discovery rate of 0.01. Our top MWAS finding, which was located in FAM63B, replicated with P = 2.3 × 10-10. It was part of the networks regulated by microRNA that can be linked to neuronal differentiation and dopaminergic gene expression. Many other top MWAS results could be linked to hypoxia and, to a lesser extent, infection, suggesting that a record of pathogenic events may be preserved in the methylome. Our findings also implicated a site in RELN, one of the most frequently studied candidates in methylation studies of schizophrenia.
To our knowledge, the present study is one of the first MWASs of disease with a large sample size using a technology that provides good coverage of methylation sites across the genome. Our results demonstrated one of the unique features of methylation studies that can capture signatures of environmental insults in peripheral tissues. Our MWAS suggested testable hypotheses about disease mechanisms and yielded biomarkers that can potentially be used to improve disease management.
Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and ...relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.
Classically derived estimates of heritability from twin models have been plagued by the possibility of genetic-environmental covariance. Survey questions that attempt to measure directly the extent ...to which more genetically similar kin (such as monozygotic twins) also share more similar environmental conditions represent poor attempts to gauge a complex underlying phenomenon of GE-covariance. The present study exploits a natural experiment to address this issue: Self-misperception of twin zygosity in the National Longitudinal Survey of Adolescent Health (Add Health). Such twins were reared under one “environmental regime of similarity” while genetically belonging to another group, reversing the typical GE-covariance and allowing bounded estimates of heritability for a range of outcomes. In addition, we examine twins who were initially misclassified by survey assignment—a stricter standard—in three datasets: Add Health, the Minnesota Twin Family Study and the Child and Adolescent Twin Study in Sweden. Results are similar across approaches and datasets and largely support the validity of the equal environments assumption.
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