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.

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.

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.

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.

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.

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.

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.

Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism.

Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10(-16)) and 1.21 (p = 2.75 × 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.

Cautious enthusiasm about GWAS findings.

In this issue of Blood, Ma and colleagues report the first agnostic investigation by a genome-wide association study (GWAS) in search of genetic determinants of a variation in plasma plasminogen levels.

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.

DNA methylation and body-mass index: a genome-wide analysis.

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 ß 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.

The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies.

The endothelial protein C receptor (EPCR) limits thrombus formation by enhancing activation of the protein C anticoagulant pathway, and therefore may play a role in the etiology of thrombotic disorders. The rs867186 single-nucleotide polymorphism in the PROCR gene (g.6936A > G, c.4600A > G), resulting in a serine-to-glycine substitution at codon 219, has been associated with reduced activation of the protein C pathway, although its association with thrombosis risk remains unclear. The present study is a highly comprehensive systematic review and meta-analysis, including unpublished genome-wide association study results, conducted to evaluate the evidence for an association between rs867186 and 2 common thrombotic outcomes, venous thromboembolism (VTE) and myocardial infarction (MI), which are hypothesized to share some etiologic pathways. MEDLINE, EMBASE, and HuGE Navigator were searched through July 2011 to identify relevant epidemiologic studies, and data were summarized using random-effects meta-analysis. Twelve candidate genes and 13 genome-wide association studies were analyzed (11 VTE and 14 MI, including 37,415 cases and 84,406 noncases). Under the additive genetic model, the odds of VTE increased by a factor of 1.22 (95% confidence interval, 1.11-1.33, P < .001) for every additional copy of the G allele. No evidence for association with MI was observed.

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 genomic architecture and association genetics of adaptive characters using a candidate SNP approach in boreal black spruce.

BACKGROUND: The genomic architecture of adaptive traits remains poorly understood in non-model plants. Various approaches can be used to bridge this gap, including the mapping of quantitative trait loci (QTL) in pedigrees, and genetic association studies in non-structured populations. Here we present results on the genomic architecture of adaptive traits in black spruce, which is a widely distributed conifer of the North American boreal forest. As an alternative to the usual candidate gene approach, a candidate SNP approach was developed for association testing. RESULTS: A genetic map containing 231 gene loci was used to identify QTL that were related to budset timing and to tree height assessed over multiple years and sites. Twenty-two unique genomic regions were identified, including 20 that were related to budset timing and 6 that were related to tree height. From results of outlier detection and bulk segregant analysis for adaptive traits using DNA pool sequencing of 434 genes, 52 candidate SNPs were identified and subsequently tested in genetic association studies for budset timing and tree height assessed over multiple years and sites. A total of 34 (65%) SNPs were significantly associated with budset timing, or tree height, or both. Although the percentages of explained variance (PVE) by individual SNPs were small, several significant SNPs were shared between sites and among years. CONCLUSIONS: The sharing of genomic regions and significant SNPs between budset timing and tree height indicates pleiotropic effects. Significant QTLs and SNPs differed quite greatly among years, suggesting that different sets of genes for the same characters are involved at different stages in the tree's life history. The functional diversity of genes carrying significant SNPs and low observed PVE further indicated that a large number of polymorphisms are involved in adaptive genetic variation. Accordingly, for undomesticated species such as black spruce with natural populations of large effective size and low linkage disequilibrium, efficient marker systems that are predictive of adaptation should require the survey of large numbers of SNPs. Candidate SNP approaches like the one developed in the present study could contribute to reducing these numbers.

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.

C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies.

Through its binding with protein S (PS), a key element of the coagulation/fibrinolysis cascade, the C4b-binding protein (C4BP) has been hypothesized to be involved in the susceptibility to venous thrombosis (VT). To identify genetic factors that may influence the plasma levels of the 3 C4BP existing isoforms, alpha(7)beta(1), alpha(6)beta(1), and alpha(7)beta(0), we conducted a genome-wide association study by analyzing 283 437 single nucleotide polymorphisms (SNPs) in the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study composed of 352 persons. Three SNPs at the C4BPB/C4BPA locus were found genome-wide significantly associated with alpha(7)beta(0) levels. One of these SNPs was further found to explain approximately 11% of the variability of mRNA C4BPA expression in the Gutenberg Heart Study composed of 1490 persons, with no effect on C4BPB mRNA expression. The allele associated with increased alpha(7)beta(0) plasma levels and increased C4BPA expression was further found associated with increased risk of VT (odds ratio [OR] = 1.24 [1.03-1.53]) in 2 independent case-control studies (MARseille THrombosis Association study [MARTHA] and FActeurs de RIsque et de récidives de la maladie thromboembolique VEineuse [FARIVE]) gathering 1706 cases and 1379 controls. This SNP was not associated with free PS or total PS. In conclusion, we observed strong evidence that the C4BPB/C4BPA locus is a new susceptibility locus for VT through a PS-independent mechanism that remains to be elucidated.

The factor XII -4C>T variant and risk of common thrombotic disorders: A HuGE review and meta-analysis of evidence from observational studies.

Coagulation factor XII is involved in thrombus formation and therefore may play a role in the etiology of thrombotic disorders. A common variant in the factor XII (F12) gene (-4C>T, rs1801020) results in decreased plasma levels of this coagulation factor. The existence of associations between low factor XII levels or F12 variants and thrombotic outcomes has been debated for more than a decade. The authors conducted a review and meta-analysis to evaluate the evidence for an association between F12 -4C>T and 2 common thrombotic outcomes: venous thromboembolism and myocardial infarction, which are hypothesized to share some etiologic pathways. MEDLINE, EMBASE, and HuGE Navigator were searched through July 2009 to identify relevant epidemiologic studies, and data were summarized using random-effects meta-analysis. Sixteen candidate gene studies (4,386 cases, 40,089 controls) were analyzed. None of the investigated contrasts reached statistical significance at P < 0.05, apart from a very weak association with myocardial infarction for the TT + CT versus CC contrast (odds ratio = 1.13, 95% confidence interval: 1.00, 1.27). Overall, based on the synthesis of observational studies, the evidence for an association between F12 -4C>T and venous thromboembolism and myocardial infarction is weak.

Combined analysis of three genome-wide association studies on vWF and FVIII plasma levels.

BACKGROUND: Elevated levels of factor VIII (FVIII) and von Willebrand Factor (vWF) are well-established risk factors for cardiovascular diseases, in particular venous thrombosis. Although high, the heritability of these traits is poorly explained by the genetic factors known so far. The aim of this work was to identify novel single nucleotide polymorphisms (SNPs) that could influence the variability of these traits. METHODS: Three independent genome-wide association studies for vWF plasma levels and FVIII activity were conducted and their results were combined into a meta-analysis totalling 1,624 subjects. RESULTS: No single nucleotide polymorphism (SNP) reached the study-wide significance level of 1.12 × 10-7 that corresponds to the Bonferroni correction for the number of tested SNPs. Nevertheless, the recently discovered association of STXBP5, STX2, TC2N and CLEC4M genes with vWF levels and that of SCARA5 and STAB2 genes with FVIII levels were confirmed in this meta-analysis. Besides, among the fifteen novel SNPs showing promising association at p < 10-5 with either vWF or FVIII levels in the meta-analysis, one located in ACCN1 gene also showed weak association (P = 0.0056) with venous thrombosis in a sample of 1,946 cases and 1,228 controls. CONCLUSIONS: This study has generated new knowledge on genomic regions deserving further investigations in the search for genetic factors influencing vWF and FVIII plasma levels, some potentially implicated in VT, as well as providing some supporting evidence of previously identified genes.

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.