Canadian COVID-19 host genetics cohort replicates known severity associations.

The HostSeq initiative recruited 10,059 Canadians infected with SARS-CoV-2 between March 2020 and March 2023, obtained clinical information on their disease experience and whole genome sequenced (WGS) their DNA. We analyzed the WGS data for genetic contributors to severe COVID-19 (considering 3,499 hospitalized cases and 4,975 non-hospitalized after quality control). We investigated the evidence for replication of loci reported by the International Host Genetics Initiative (HGI); analyzed the X chromosome; conducted rare variant gene-based analysis and polygenic risk score testing. Population stratification was adjusted for using meta-analysis across ancestry groups. We replicated two loci identified by the HGI for COVID-19 severity: the LZTFL1/SLC6A20 locus on chromosome 3 and the FOXP4 locus on chromosome 6 (the latter with a variant significant at P < 5E-8). We found novel significant associations with MRAS and WDR89 in gene-based analyses, and constructed a polygenic risk score that explained 1.01% of the variance in severe COVID-19. This study provides independent evidence confirming the robustness of previously identified COVID-19 severity loci by the HGI and identifies novel genes for further investigation.

COVID-19 Pandemic, Physical Distancing Policies, and the Non-Profit Sector Volunteer Force.

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.

Child health and its effect on adult social capital accumulation.

Although studies have demonstrated important effects of poor health in childhood on stocks of human and health capital, little research has tested economic theories to investigate the effect of child health on social capital in adulthood. Studies on the influence of child health on adult social capital are mixed and have not used sibling fixed effects models to account for unmeasured family and genetic characteristics, that are likely to be important. Using the Add-Health sample, health in childhood was assessed as self-rated health, the occurrence of a physical health condition or mental health condition, while social capital in adulthood was measured as volunteering, religious service attendance, team sports participation, number of friends, social isolation, and social support. We used sibling fixed effects models, which attenuated several associations to non-significance. In sibling fixed effects models there was significant positive effects of greater self-rated health on participation in team sports and social support, and negative effect of mental health in childhood on social isolation in adulthood. These results suggest that children with poor health require additional supports to build and maintain their stock of social capital and highlight further potential benefits to efforts that address poor child health.

Genetic endowments for social capital: An investigation accounting for genetic nurturing effects.

Despite social capital having been shown to be important for health and well-being, relatively little research has examined genetic determinants. Genetic endowments for education have been shown to influence human, financial, and health capital, but few studies have examined social capital, and those conducted have yet to account for genetic nurturing. We used the Add-Health data to study the effect of genetic endowments on individual social capital using the education polygenic score (PGS). We used sibling fixed effects models and controlled for the family environment to account for genetic nurturing. After accounting for the family environment, we found moderately large significant associations between the education PGS and volunteering, but associations with religious service attendance and number of friends were completely attenuated in sibling fixed effects models. These findings highlight that genetic endowments play an important role in influencing volunteering and the importance of accounting for genetic nurturing.

The mental health impact of the COVID-19 pandemic on post-secondary students: A longitudinal study.

This prospective longitudinal study measured sex-specific changes in depression, anxiety, and stress scores using, validated Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and the Perceived Stress Scale (PSS) in a cohort of 1445 post-secondary students (500 males, 945 females) assessed at three time points from December 2020 to January 2022. Participants were ascertained from a population of 15,585 students with in-person activities on campus at baseline and recruited from December 2020 to January 2021. We also assessed how sociodemographic characteristics influenced students' mental health outcomes. Inverse probability weighting was used to account for missing data and attrition. Linear mixed effects models were used to analyze the relationship between the mental health scores in each questionnaire, demographic and academic data, and public health stringency measured by the local stringency index. No change was observed in questionnaire scores over time for males and females, but the stringency index was significantly associated with increased stress. Being in a non-health-related-field or being white affected males and females differently for stress and anxiety, but not depression. Demographics tended to be more influential on females' mental health than males. In conclusion, mental health resource allocation in time of emerging pandemic could benefit from targeted interventions.

Issue Competition and the Social Construction of Target Populations: Alternative Suggestions for the Study of the Influence of Populist Radical Right Parties on Health Policy and Health Outcomes Comment on "A Scoping Review of Populist Radical Right Parties' Influence on Welfare Policy and its Implications for Population Health in Europe".

Rinaldi and Bekker ask whether populist radical right (PRR) parties have an influence on population health and health equity. The assumption is that this influence is negative, but mediated by political system characteristics. Starting from the authors' premise that the positions of PRR parties on welfare policies are a good proxy for health outcomes, we build on political science literature to suggest further avenues for research. The equivocal relationship between political parties and the ownership of specific healthcare, health insurance and public health issues invites studies that break down party positions relating to different health policy issues. As policy-makers use social representations of target populations to make policy decisions and anticipate the feedback these decisions might generate, it is worth studying how PRR parties influence societal, institutional and partisan perceptions of deserving and undeserving populations, even when they are not in government.

Statistical power in COVID-19 case-control host genomic study design.

The identification of genetic variation that directly impacts infection susceptibility to SARS-CoV-2 and disease severity of COVID-19 is an important step towards risk stratification, personalized treatment plans, therapeutic, and vaccine development and deployment. Given the importance of study design in infectious disease genetic epidemiology, we use simulation and draw on current estimates of exposure, infectivity, and test accuracy of COVID-19 to demonstrate the feasibility of detecting host genetic factors associated with susceptibility and severity in published COVID-19 study designs. We demonstrate that limited phenotypic data and exposure/infection information in the early stages of the pandemic significantly impact the ability to detect most genetic variants with moderate effect sizes, especially when studying susceptibility to SARS-CoV-2 infection. Our insights can aid in the interpretation of genetic findings emerging in the literature and guide the design of future host genetic studies.

A catalog of annotated high-confidence SNPs from exome capture and sequencing reveals highly polymorphic genes in Norway spruce (Picea abies).

BACKGROUND: Norway spruce [Picea abies (L.) Karst.] is ecologically and economically one of the most important conifer worldwide. Our main goal was to develop a large catalog of annotated high confidence gene SNPs that should sustain the development of genomic tools for the conservation of natural and domesticated genetic diversity resources, and hasten tree breeding efforts in this species. RESULTS: Targeted sequencing was achieved by capturing P. abies exome with probes previously designed from the sequenced transcriptome of white spruce (Picea glauca (Moench) Voss). Capture efficiency was high (74.5%) given a high level of exome conservation between the two species. Using stringent criteria, we delimited a set of 61,771 high-confidence SNPs across 13,543 genes. To validate SNPs, a high-throughput genotyping array was developed for a subset of 5571 predicted SNPs representing as many different gene loci, and was used to genotype over 1000 trees. The estimated true positive rate of the resource was 84.2%, which was comparable with the genotyping success rate obtained for P. abies control SNPs recycled from previous genotyping efforts. We also analyzed SNP abundance across various gene functional categories. Several GO terms and gene families involved in stress response were found over-represented in highly polymorphic genes. CONCLUSION: The annotated high-confidence SNP catalog developed herein represents a valuable genomic resource, being representative of over 13 K genes distributed across the P. abies genome. This resource should serve a variety of population genomics and breeding applications in Norway spruce.

DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis.

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 × 10-5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

Validation of the evaluation capacity in organizations questionnaire.

The purpose of this study was to test the construct validity of the Evaluation Capacity in Organizations Questionnaire (ECOQ). Conceptually, the ECOQ examines the role of evaluation in organizational development and, most notably in organizational learning. In this model, evaluation capacity building (ECB) initiatives are assumed to contribute to the development of a culture of systematic self-assessment and reflection, which, in turn, leads to increased organizational learning. Our sample consisted of internal evaluators within the federal, provincial or municipal government, not-for-profit organizations, private firms, and colleges or universities in Canada. Exploratory factor analysis (EFA) and latent path analysis (LPA) were conducted to better understand the underlying structural aspect of the organizational capacity to do and use evaluation construct as measured by the ECOQ. The results of our study indicate that the ECOQ effectively assesses an organization's capacity to do and use evaluation. Furthermore, evidence provided by the LPA statistical analysis suggests that an organization's capacity to learn is enhanced by the relationships among the various factors. Implications of using a validated model of an organization's capacity to do and use evaluations in both research and practice are discussed.

Homocysteine levels associate with subtle changes in leukocyte DNA methylation: an epigenome-wide analysis.

AIM: Homocysteine (Hcy) is a sensitive marker of one-carbon metabolism. Higher Hcy levels have been associated with global DNA hypomethylation. We investigated the association between plasma Hcy and epigenome-wide DNA methylation in leukocytes. METHODS: Methylation was measured using Illumina 450 k arrays in 2035 individuals from six cohorts. Hcy-associated differentially methylated positions and regions were identified using meta-analysis. RESULTS: Three differentially methylated positions cg21607669 (SLC27A1), cg26382848 (AJUBA) and cg10701000 (KCNMA1) at chromosome 19, 14 and 10, respectively, were significantly associated with Hcy. In addition, we identified 68 Hcy-associated differentially methylated regions, the most significant of which was a 1.8-kb spanning domain (TNXB/ATF6B) at chromosome 6. CONCLUSION: We identified novel epigenetic loci associated with Hcy levels, of which specific role needs to be further validated.

Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes.

BACKGROUND: DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. METHODS: Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. RESULTS: Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. CONCLUSIONS: Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.

Blood triglyceride levels are associated with DNA methylation at the serine metabolism gene PHGDH.

Efficient interventions to reduce blood triglycerides are few; newer and more tolerable intervention targets are needed. Understanding the molecular mechanisms underlying blood triglyceride levels variation is key to identifying new therapies. To explore the role of epigenetic mechanisms on triglyceride levels, a blood methylome scan was conducted in 199 individuals from 5 French-Canadian families ascertained on venous thromboembolism, and findings were replicated in 324 French unrelated patients with venous thromboembolism. Genetic context and functional relevance were investigated. Two DNA methylation sites associated with triglyceride levels were identified. The first one, located in the ABCG1 gene, was recently reported, whereas the second one, located in the promoter of the PHGDH gene, is novel. The PHGDH methylation site, cg14476101, was found to be associated with variation in triglyceride levels in a threshold manner: cg14476101 was inversely associated with triglyceride levels only when triglyceride levels were above 1.12 mmol/L (discovery P-value = 8.4 × 10-6; replication P-value = 0.0091). Public databases findings supported a functional role of cg14476101 on PHGDH expression. PHGDH catalyses the first step in the serine biosynthesis pathway. These findings highlight the role of epigenetic regulation of the PHGDH gene in triglyceride metabolism, providing novel insights on putative intervention targets.

Why and How Political Science Can Contribute to Public Health? Proposals for Collaborative Research Avenues.

Written by a group of political science researchers, this commentary focuses on the contributions of political science to public health and proposes research avenues to increase those contributions. Despite progress, the links between researchers from these two fields develop only slowly. Divergences between the approach of political science to public policy and the expectations that public health can have about the role of political science, are often seen as an obstacle to collaboration between experts in these two areas. Thus, promising and practical research avenues are proposed along with strategies to strengthen and develop them. Considering the interdisciplinary and intersectoral nature of population health, it is important to create a critical mass of researchers interested in the health of populations and in healthy public policy that can thrive working at the junction of political science and public health.

Sex-specific effect of CPB2 Ala147Thr but not Thr325Ile variants on the risk of venous thrombosis: A comprehensive meta-analysis.

BACKGROUND: Thrombin activatable fibrinolysis inhibitor (TAFI), encoded by the Carboxypeptidase B2 gene (CPB2), is an inhibitor of fibrinolysis and plays a role in the pathogenesis of venous thrombosis. Experimental findings support a functional role of genetic variants in CPB2, while epidemiological studies have been unable to confirm associations with risk of venous thrombosis. Sex-specific effects could underlie the observed inconsistent associations between CPB2 genetic variants and venous thrombosis. METHODS: A comprehensive literature search was conducted for associations between Ala147Thr and Thr325Ile variants with venous thrombosis. Authors were contacted to provide sex-specific genotype counts from their studies. Combined and sex-specific random effects meta-analyses were used to estimate a pooled effect estimate for primary and secondary genetic models. RESULTS: A total of 17 studies met the inclusion criteria. A sex-specific meta-analysis applying a dominant model supported a protective effect of Ala147Thr on venous thrombosis in females (OR = 0.81, 95%CI: 0.68,0.97; p = 0.018), but not in males (OR = 1.06, 95%CI:0.96-1.16; p = 0.263). The Thr325Ile did not show a sex-specific effect but showed variation in allele frequencies by geographic region. A subgroup analysis of studies in European countries showed decreased risk, with a recessive model (OR = 0.83, 95%CI:0.71-0.97, p = 0.021) for venous thrombosis. CONCLUSIONS: A comprehensive literature review, including unpublished data, provided greater statistical power for the analyses and decreased the likelihood of publication bias influencing the results. Sex-specific analyses explained apparent discrepancies across genetic studies of Ala147Thr and venous thrombosis. While, careful selection of genetic models based on population genetics, evolutionary and biological knowledge can increase power by decreasing the need to adjust for testing multiple models.

Leveraging cell type specific regulatory regions to detect SNPs associated with tissue factor pathway inhibitor plasma levels.

Tissue factor pathway inhibitor (TFPI) regulates the formation of intravascular blood clots, which manifest clinically as ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). TFPI plasma levels are heritable, but the genetics underlying TFPI plasma level variability are poorly understood. Herein we report the first genome-wide association scan (GWAS) of TFPI plasma levels, conducted in 251 individuals from five extended French-Canadian Families ascertained on VTE. To improve discovery, we also applied a hypothesis-driven (HD) GWAS approach that prioritized single nucleotide polymorphisms (SNPs) in (1) hemostasis pathway genes, and (2) vascular endothelial cell (EC) regulatory regions, which are among the highest expressers of TFPI. Our GWAS identified 131 SNPs with suggestive evidence of association (P-value < 5 × 10-8 ), but no SNPs reached the genome-wide threshold for statistical significance. Hemostasis pathway genes were not enriched for TFPI plasma level associated SNPs (global hypothesis test P-value = 0.147), but EC regulatory regions contained more TFPI plasma level associated SNPs than expected by chance (global hypothesis test P-value = 0.046). We therefore stratified our genome-wide SNPs, prioritizing those in EC regulatory regions via stratified false discovery rate (sFDR) control, and reranked the SNPs by q-value. The minimum q-value was 0.27, and the top-ranked SNPs did not show association evidence in the MARTHA replication sample of 1,033 unrelated VTE cases. Although this study did not result in new loci for TFPI, our work lays out a strategy to utilize epigenomic data in prioritization schemes for future GWAS studies.

A high-resolution reference genetic map positioning 8.8 K genes for the conifer white spruce: structural genomics implications and correspondence with physical distance.

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.

Genome-wide association study with additional genetic and post-transcriptional analyses reveals novel regulators of plasma factor XI levels.

Coagulation factor XI (FXI) has become increasingly interesting for its role in pathogenesis of thrombosis. While elevated plasma levels of FXI have been associated with venous thromboembolism and ischemic stroke, its deficiency is associated with mild bleeding. We aimed to determine novel genetic and post-transcriptional plasma FXI regulators.We performed a genome-wide association study (GWAS) for plasma FXI levels, using novel data imputed to the 1000 Genomes reference panel. Individual GWAS analyses, including a total of 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analysed and further replicated in 2,045 individuals from the F5L family, GAIT2 and MEGA studies. Additional association with activated partial thromboplastin time (aPTT) was tested for the top SNPs. In addition, a study on the effect of miRNA on FXI regulation was performed using in silico prediction tools and in vitro luciferase assays.Three loci showed robust, replicating association with circulating FXI levels: KNG1 (rs710446, P-value = 2.07 × 10-302), F11 (rs4253417, P-value = 2.86 × 10-193), and a novel association in GCKR (rs780094, P-value = 3.56 ×10-09), here for the first time implicated in FXI regulation. The two first SNPs (rs710446 and rs4253417) also associated with aPTT. Conditional and haplotype analyses demonstrated a complex association signal, with additional novel SNPs modulating plasma FXI levels in both the F11 and KNG1 loci. Finally, eight miRNAs were predicted to bind F11 mRNA. Over-expression of either miR-145 or miR-181 significantly reduced the luciferase activity in cells transfected with a plasmid containing FXI-3'UTR.These results should open the door to new therapeutic targets for thrombosis prevention.

Development of highly reliable in silico SNP resource and genotyping assay from exome capture and sequencing: an example from black spruce (Picea mariana).

Picea mariana is a widely distributed boreal conifer across Canada and the subject of advanced breeding programmes for which population genomics and genomic selection approaches are being developed. Targeted sequencing was achieved after capturing P. mariana exome with probes designed from the sequenced transcriptome of Picea glauca, a distant relative. A high capture efficiency of 75.9% was reached although spruce has a complex and large genome including gene sequences interspersed by some long introns. The results confirmed the relevance of using probes from congeneric species to perform successfully interspecific exome capture in the genus Picea. A bioinformatics pipeline was developed including stringent criteria that helped detect a set of 97,075 highly reliable in silico SNPs. These SNPs were distributed across 14,909 genes. Part of an Infinium iSelect array was used to estimate the rate of true positives by validating 4267 of the predicted in silico SNPs by genotyping trees from P. mariana populations. The true positive rate was 96.2% for in silico SNPs, compared to a genotyping success rate of 96.7% for a set 1115 P. mariana control SNPs recycled from previous genotyping arrays. These results indicate the high success rate of the genotyping array and the relevance of the selection criteria used to delineate the new P. mariana in silico SNP resource. Furthermore, in silico SNPs were generally of medium to high frequency in natural populations, thus providing high informative value for future population genomics applications.

Association of the APOE-ε4 allele with outcome of traumatic brain injury in children and youth: a meta-analysis and meta-regression.

OBJECTIVE: To disentangle the temporal relationship between the APOE-ε4 allele and outcomes of paediatric traumatic brain injury (TBI). METHODS: PubMed, EMBASE, Web of Science, MEDLINE, PsychINFO and HuGE Navigator Genopedia databases were searched from their inception up to January 2015 without language limitations. Included studies were analysed under a dominant genetic model to assess the association between the APOE-ε4 allele and poor outcomes of paediatric TBI at 6 months. Meta-regression was used to assess trends over time. RESULTS: Of the 325 initially identified records, 6 studies were selected and analysed based on inclusion/exclusion criteria. A total of 358 cases of paediatric TBI were included. 2 studies assessed outcomes at multiple time points ranging from 3 to 36 months; 4 studies assessed outcomes at a single time point (either 6 or 12 months). At 6 months, there is 2.36 (95% CI 1.26 to 4.42; p=0.007) times higher odds of poor outcome following TBI in children with at least one APOE-ε4 allele, compared with the children without. Further, the adjusted odds suggested an increasing trend of 7% per month (95% CI -9 to 25; p=0.359). CONCLUSIONS: This meta-analysis provides cumulative evidence that the APOE-ε4 allele is important to the prognosis of paediatric TBI, but may have a different effect compared with adult TBI; moreover, this effect may be time dependent.