Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of ...DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
Although COVID-19-related physical distancing has had large economic consequences, the impact on volunteerism is unclear. Using volunteer position postings data from Canada’s largest volunteer center ...(Volunteer Toronto) from February 3, 2020, to January 4, 2021, we evaluated the impact of different levels of physical distancing on average views, total views, and total number of posts. There was about a 50% decrease in the total number of posts that was sustained throughout the pandemic. Although a more restrictive physical distancing policy was generally associated with fewer views, there was an initial increase in views during the first lockdown where total views were elevated for the first 4 months of the pandemic. This was driven by interest in COVID-19-related and remote work postings. This highlights the community of volunteers may be quite flexible in terms of adapting to new ways of volunteering, but substantial challenges remain for the continued operations of many non-profit organizations.
Objectives. This study was undertaken to determine whether lipoprotein(a) Lp(a) is an independent risk factor for ischemic heart disease (IHD) and to establish the relation of Lp(a) to the other ...lipid fractions.
Background. Several, but not all, studies have shown that elevated Lp(a) concentrations may be associated with IHD; very few have been prospective.
Methods. A 5-year prospective follow-up study was conducted in 2,156 French Canadian men 47 to 76 years old, without clinical evidence of IHD. Lipid measurements obtained at baseline included total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, apoprotein B and Lp(a). During the follow-up period, there were 116 first IHD events (myocardial infarction, angina, death). Adjusted proportional hazards models were used to estimate the relative risk for the different variables. The cohort was also classified according to Lp(a) levels and other lipid risk factor tertiles to evaluate the relation of elevated Lp(a) levels to these risk factors. A cutoff value of 30 mg/dl was used for Lp(a). Risk ratios were calculated using the group with low Lp(a) levels and the first tertile of lipid measures as a reference.
Results. Lp(a) was not an independent risk factor for IHD but seemed to increase the deleterious effects of mildly elevated LDL cholesterol and elevated total cholesterol and apoprotein B levels and seemed to counteract the beneficial effects associated with elevated HDL cholesterol levels.
Conclusions. In this cohort, Lp(a) was not an independent risk factor for IHD but appeared to increase the risk associated with other lipid risk factors.
•A complex mix of factors contributed to opening a policy window for a soda tax in France in 2011.•Facilitators included a tense economic situation, available tax schemes and political will.•Along ...the formulation, budgetary considerations took precedence over public health motivations.•A stepwise dialogue among stakeholders may favour smart compromises in the design of a soda tax.•Such analyses can help to understand, inform and influence public health policy-making.
Although over 40 jurisdictions have adopted a tax on sugar-sweetened beverages (SSBs) for public health worldwide, it is still debated in many places. Policy processes can influence the prospect of an SSB tax, its design and its public health benefits. To get an insight into such processes, we undertook a case study of the soda tax enacted in France on the 1st of January 2012. Newspaper articles (2003–2013) and institutional documents (2007–2012) were identified using keywords and search engines. Qualitative data extraction and analyses were performed on a thematic and chronological basis, with guidance from Kingdon’s multiple streams theory (MST). Triangulation was enhanced by using complementary sources. This study shows that in August 2011, the French government surprisingly announced a €3.58 cent/L excise tax on SSBs, excluding juices with no added sugars and non-calorically sweetened beverages (NCSBs). As part of a large budgetary plan, the proposal aimed to reduce SSB consumption and raise revenue that was earmarked for health care. Several conditions contributed to opening a policy window: The announcement occurred in the context of severe budgetary deficits; soda tax scenarios had already been discussed at a high level; and the bill was supported by convinced political leaders. Subsequently, the tax successfully passed through the legislative process due to a series of unexpected events, but its public health rationale and design were weakened. The first event was the disorganised reaction by the food industry, despite their sharp opposition to the tax. The next event was the support of the soda tax that came from a majority of Deputies, provided that the revenues would serve another purpose: relieving wage costs in the farming sector. Finally, policy entrepreneurs favoured a compromise to make the tax politically acceptable and legally viable: The tax rate doubled, the scope was extended to NCSBs and revenues were split between health care and agriculture. This study sheds light on influence factors that could be taken into account by public health actors willing to influence soda tax policy processes.
Summary
Over the last decade, extensive genetic and genomic resources have been developed for the conifer white spruce (Picea glauca, Pinaceae), which has one of the largest plant genomes (20 Gbp). ...Draft genome sequences of white spruce and other conifers have recently been produced, but dense genetic maps are needed to comprehend genome macrostructure, delineate regions involved in quantitative traits, complement functional genomic investigations, and assist the assembly of fragmented genomic sequences. A greatly expanded P. glauca composite linkage map was generated from a set of 1976 full‐sib progeny, with the positioning of 8793 expressed genes. Regions with significant low or high gene density were identified. Gene family members tended to be mapped on the same chromosomes, with tandemly arrayed genes significantly biased towards specific functional classes. The map was integrated with transcriptome data surveyed across eight tissues. In total, 69 clusters of co‐expressed and co‐localising genes were identified. A high level of synteny was found with pine genetic maps, which should facilitate the transfer of structural information in the Pinaceae. Although the current white spruce genome sequence remains highly fragmented, dozens of scaffolds encompassing more than one mapped gene were identified. From these, the relationship between genetic and physical distances was examined and the genome‐wide recombination rate was found to be much smaller than most estimates reported for angiosperm genomes. This gene linkage map shall assist the large‐scale assembly of the next‐generation white spruce genome sequence and provide a reference resource for the conifer genomics community.
Significance Statement
Conifers have very large genomes whose macrostructure is still poorly understood. Here we developed a greatly expanded reference genetic map for white spruce. Gene marker density and accuracy of this map are high, synteny with pine genetic maps is high and segregating regions underlying quantitative trait variation were well populated with genes. Genome sequence scaffolds and transcriptome information were anchored on the genetic map, thus providing a highly relevant resource for future conifer genome research.
Summary Background Obesity is a major health problem that is determined by interactions between lifestyle and environmental and genetic factors. Although associations between several genetic variants ...and body-mass index (BMI) have been identified, little is known about epigenetic changes related to BMI. We undertook a genome-wide analysis of methylation at CpG sites in relation to BMI. Methods 479 individuals of European origin recruited by the Cardiogenics Consortium formed our discovery cohort. We typed their whole-blood DNA with the Infinium HumanMethylation450 array. After quality control, methylation levels were tested for association with BMI. Methylation sites showing an association with BMI at a false discovery rate q value of 0·05 or less were taken forward for replication in a cohort of 339 unrelated white patients of northern European origin from the MARTHA cohort. Sites that remained significant in this primary replication cohort were tested in a second replication cohort of 1789 white patients of European origin from the KORA cohort. We examined whether methylation levels at identified sites also showed an association with BMI in DNA from adipose tissue (n=635) and skin (n=395) obtained from white female individuals participating in the MuTHER study. Finally, we examined the association of methylation at BMI-associated sites with genetic variants and with gene expression. Findings 20 individuals from the discovery cohort were excluded from analyses after quality-control checks, leaving 459 participants. After adjustment for covariates, we identified an association (q value ≤0·05) between methylation at five probes across three different genes and BMI. The associations with three of these probes—cg22891070, cg27146050, and cg16672562, all of which are in intron 1 of HIF3A —were confirmed in both the primary and second replication cohorts. For every 0·1 increase in methylation β value at cg22891070, BMI was 3·6% (95% CI 2·4–4·9) higher in the discovery cohort, 2·7% (1·2–4·2) higher in the primary replication cohort, and 0·8% (0·2–1·4) higher in the second replication cohort. For the MuTHER cohort, methylation at cg22891070 was associated with BMI in adipose tissue (p=1·72 × 10−5 ) but not in skin (p=0·882). We observed a significant inverse correlation (p=0·005) between methylation at cg22891070 and expression of one HIF3A gene-expression probe in adipose tissue. Two single nucleotide polymorphisms—rs8102595 and rs3826795—had independent associations with methylation at cg22891070 in all cohorts. However, these single nucleotide polymorphisms were not significantly associated with BMI. Interpretation Increased BMI in adults of European origin is associated with increased methylation at the HIF3A locus in blood cells and in adipose tissue. Our findings suggest that perturbation of hypoxia inducible transcription factor pathways could have an important role in the response to increased weight in people. Funding The European Commission, National Institute for Health Research, British Heart Foundation, and Wellcome Trust.
MYC
-rearranged B-cell lymphoma (BCL) in the pediatric/young adult (YA) age group differs substantially in disease composition from adult cohorts. However, data regarding the partner genes, ...concurrent rearrangements, and ultimate diagnoses in these patients is scarce compared to that in adult cohorts. We aimed to characterize the spectrum of
MYC
-rearranged (
MYC
-R) mature, aggressive BCL in the pediatric/YA population. A retrospective study of morphologic, immunophenotypic, and fluorescence in situ hybridization (FISH) results of patients age ≤ 30 years with suspected Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL), and a
MYC
-R by FISH between 2013–2022 was performed. Two-hundred fifty-eight cases (129 (50%) pediatric (< 18 years) and 129 (50%) YA (18–30 years)) were included. Most
MYC
-R BCL in pediatric (89%) and YA (66%) cases were BL. While double-hit (DH) cytogenetics (
MYC
with
BCL2
and/or
BCL6
-R, HGBCL-DH) was rare in the pediatric population (2/129, 2%), HGBCL-DH increased with age and was identified in 17/129 (13%) of YA cases. Most HGBCL-DH had
MYC
and
BCL6
-R, while
BCL2
-R were rare in both groups (3/258, 1%).
MYC
-R without an IG partner was more common in the YA group (14/116 (12%) vs 2/128 (2%),
p
= 0.001). The pediatric to YA transition is characterized by decreasing frequency in BL and increasing genetic heterogeneity of
MYC
-R BCL, with emergence of DH-BCL with
MYC
and
BCL6
-R. FISH to evaluate for
BCL2
and
BCL6
rearrangements is likely not warranted in the pediatric population but should continue to be applied in YA BCL.
Myeloid/lymphoid neoplasms with
gene fusions have recently been included among myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) in the World Health Organization ...classification and International Consensus Classification. As this entity remains remarkably rare, its scope and phenotypic features are evolving. In this report, we describe a 33-yr-old male with MLN-TK. Conventional chromosome analysis revealed a t(13;14)(q12;q32). Further analysis with mate-pair sequencing (MPseq) confirmed a
gene fusion. A diagnosis of MLN-TK was rendered. To the best of our knowledge, we report the third case of MLN-TK with a
gene fusion. In contrast to previously described cases, our case exhibited distinctly mild clinical features and disease behavior, emphasizing the diverse spectrum of MLN-TK at primary presentation and variability in disease course. MLN-TK with
gene fusions are a genetically defined entity which may be targetable with tyrosine kinase inhibitors with anti-FLT3 activity. Accordingly, from diagnostic and therapeutic viewpoints, genetic testing for
rearrangements using fluorescence in situ hybridization (FISH) or sequencing-based assays should be pursued for patients with chronic eosinophilia.
Abstract Much medical research is observational. The reporting of observational studies is often of insufficient quality. Poor reporting hampers the assessment of the strengths and weaknesses of a ...study and the generalisability of its results. Taking into account empirical evidence and theoretical considerations, a group of methodologists, researchers, and editors developed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations to improve the quality of reporting of observational studies. The STROBE Statement consists of a checklist of 22 items, which relate to the title, abstract, introduction, methods, results and discussion sections of articles. Eighteen items are common to cohort studies, case–control studies and cross-sectional studies and four are specific to each of the three study designs. The STROBE Statement provides guidance to authors about how to improve the reporting of observational studies and facilitates critical appraisal and interpretation of studies by reviewers, journal editors and readers. This explanatory and elaboration document is intended to enhance the use, understanding, and dissemination of the STROBE Statement. The meaning and rationale for each checklist item are presented. For each item, one or several published examples and, where possible, references to relevant empirical studies and methodological literature are provided. Examples of useful flow diagrams are also included. The STROBE Statement, this document, and the associated Web site ( http://www.strobe-statement.org/ ) should be helpful resources to improve reporting of observational research.
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