European Samples Research Articles

Stress Resilience And Resilience Factors Across 9 European Samples During The COVID-19 Pandemic

Abstract While many describe changes in mental health over the pandemic, we investigate change in resilience over time during the pandemic. Stress resilience can be operationalised as stressor reactivity, that is, how much a person’s mental health is affected by the stressors that they experience. Utilising the individual participant data (IPD) meta-analyses megadataset available we first define and quantify how many stressors individuals. We then regress this stressor exposure on mental health within each sample to compute each sample’s normative stressor reactivity. Each person’s individual stressor reactivity is then calculated as the residual to this line at each time points. Resilient outcomes can be understood as lower reactivity as this indicates lower susceptibility to stressors. Stressor reactivity (SR) scores control for individual stressor exposure, therefore allowing us to investigate resilience factors during a time in which exposure to macro and micro stressors varied greatly between individuals. Further, SR scores are a harmonised outcome that can easily compared across different samples in the IPD dataset. Using this outcome, we present findings on resilience trajectories and identify factors that are associated with resilient outcomes. We also disentangle the role of current stressor exposure and prior stressors, showing that prior exposure to stressors increases vulnerability in subsequent exposures. Our findings show that stressor reactivity over time was more stable than mental health symptoms during the pandemic, therefore indicating that SR as an outcome offers new insights into the impact of the pandemic.

Loneliness in the elderly and disease development in European welfare regions: a longitudinal study

Abstract Healthy ageing research has brought a recent focus on the association between loneliness and disease. Regional differences on loneliness prevalence in the elderly across welfare systems, and its association with varying mortality rates, have recently been demonstrated. We hypothesise loneliness affects disease development in the elderly, impacted by socio-economic policies that characterise welfare systems in the EU. We use logistic regression models to assess the association between loneliness (R-UCLA scale) and onset of new chronic disease and disease events, in a European sample of people aged >50 (n = 40840), using the SHARE database, during 2013 - 22 (waves 5 to 9). Preliminary results from two subsequent waves (2015-17, n = 11870) show a statistically significant effect of persistent loneliness on disease onset (increase in new disease events), when adjusting for sex, age, previous illness, and other socio-economic covariates (AOR 1.22, 95%CI 1.08-1.39, p < 0.01). Notably, comparing to the Scandinavian welfare group, only Eastern European countries show higher odds of disease development (AOR 1.52, 95%CI 1.32-1.77, p < 0.001), while also having the highest incidence of new disease in our sample. Age and welfare group show the strongest association with the outcome of interest, followed by change in occupation (no longer employed). Our current analyses span a larger period (2013-22), and we are exploring additional mediators of this effect, such as behavioural and social activity-related variables. Additional analyses to control for unrelated disease (low biological plausibility) and a social isolation index, described in the literature, are added. Furthermore, we analyse the longitudinal association between loneliness and healthcare use, such as polypharmacy and consults. With this study, we aim to contribute decision-making in health in all policies, by increasing integration between health and social sectors, while considering different regional and welfare policies. Key messages • Understanding socio-economic and welfare mechanisms which impact health in the elderly allows for better cross-sector policy design, promoting healthier ageing. • Persistent feelings of loneliness affect disease development in the elderly, which appear to be worsened in some EU welfare groups, independently of socio-economic status.

The mendelian randomized study revealed the association of prostatitis with prostate cancer risk

In recent observational studies, a potential link between prostatitis and prostate cancer (PCa) has been hinted at, yet the causality remains ambiguous. In our endeavor to scrutinize the conceivable causal nexus between prostatitis and PCa, we embarked upon a Mendelian randomization (MR) study. MR circumvents arbitrary groupings by employing genetic variations that have a strong association with the exposure as instrumental variables to infer causal relationships between exposures and outcomes. The etiology of PCa remains elusive. Given that prostatitis and prostate cancer occupy the same anatomical region, MR can more effectively delineate their relationship by mitigating confounding variables. This method can indirectly elucidate disease correlations, thereby contributing to cancer prevention strategies. FinnGen Consortium data were used for the prostatitis genome-wide association study (GWAS), including 74,658 participants. UK biobank baseline data (ncase = 3436, ncontrol = 459574), European Bioinformatics Institute Database (ncase = 79148, ncontrol = 61106), and IEU openGWAS database (ncase = 79148, ncontrol = 61106) were used for PCa outcomes, mostly for European population samples. Data from the GWSAs for prostatitis were compared with data from the three GWASs for PCa, respectively, in an analysis of an MR. Utilizing the inverse variance weighting (IVW) methodology as our primary analytical framework, we delved into a meticulous exploration of the conceivable causal association between prostatitis and PCa. Furthermore, we deployed supplementary methodologies, including Maximum Likelihood, MR-Egger, weighted median, and MR-PRESSO, to thoroughly assess and scrutinize the causality aspect comprehensively. Cochran’s Q statistic is employed as a metric to quantify the heterogeneity inherent in instrumental variables. The inverse variance weighted analysis revealed no discernible effect of prostatitis on PCa in the three PCa GWAS databases (odds ratio [OR]: 1.001, 95% Confidence Interval [CI]: 0.999–1.002, p = 0.28), (OR: 1.015, 95% CI: 0.981–1.050, p = 0.40), (OR: 1.015, 95% CI: 0.981–1.050, p = 0.40). Similarly, employing MR-Egger did not yield substantial evidence (OR: 0.999, 95% CI: 0.999–1.002, p = 0.89), (OR: 1.103, 95% CI: 1.006–1.209, p = 0.07), (OR: 1.103, 95% CI: 1.006–1.209, p = 0.07). The weighted median analysis also failed to provide convincing support for the impact of prostatitis on the incidence of PCa (OR: 1.001, 95% CI: 1.000-1.002, p = 0.064), (OR: 0.989, 95% CI: 0.946–1.034, p = 0.64), (OR: 0.989, 95% CI: 0.945–1.036, p = 0.65). The results of the MR showed no causality from prostatitis to PCa.

Genome sequence of a European Diplocarpon coronariae strain and in silico structure of the mating-type locus

Diplocarpon coronariae is a fungal pathogen that is prevalent in low-input apple production. Over the past 15 years, it has become increasingly distributed in Europe. However, comprehensive insights into its biology and pathogenicity remain limited. One particular aspect is the rarity of the sexual morph of this pathogen, a phenomenon hitherto unobserved in Europe. Diplocarpon coronariae reproduces through a heterothallic mating system requiring at least two different mating types for sexual reproduction. Genes determining the mating types are located on the mating-type locus. In this study, D. coronariae strain DC1_JKI from Dresden, Germany, was sequenced and used to unravel the structure of the mating type locus. Using short-read and long-read sequencing methods, the first gapless and near-complete telomere-to-telomere genome assembly of D. coronariae was achieved. The assembled genome spans 51.2 Mbp and comprises 21 chromosome-scale contigs of high completeness. The generated genome sequence was used to in silico elucidate the structure of the mating-type locus, identified as MAT1-2. Furthermore, an examination of MAT1-1 and MAT1-2 frequency across a diverse set of samples sourced from Europe and Asia revealed the exclusive presence of MAT1-2 in European samples, whereas both MAT loci were present in Asian counterparts. Our findings suggest an explanation for the absence of the sexual morph, potentially linked to the absence of the second mating idiomorph of D. coronariae in European apple orchards.

Screening for contamination with genetically modified organisms in food, feed and their additives obtained in retail and online shops in Latvia

The aim of the study was to screen for contamination of food and feed products with genetically modified organisms (GMO) in several sample groups obtained from retail and online shops. The total number of samples was 171, including 67 of food, 26 feed, 27 additive, and 51 samples of dried pollen for human consumption. Detection and quantification of GMO in food and feed was performed according to the approved quantitative real-time PCR methods. Fermentation product samples were analyzed using screening for antimicrobial resistance genes, 16S RNA and ITS1 sequencing, isolation of bacterial cultures and whole genome sequencing. In total, GMO contamination was found in 12 samples (in 10.45% of food and in 19.23% of feed samples). A lower proportion of GMO containing samples were from the European Union (10.26 %) vs. samples from outside (17.02%), but none with ingredients of both origins. Non-compliant were three food and five feed samples. Of the 27 samples of food and feed additives and food supplements, 10 samples were possibly non-compliant, as they contained live bacteria with antimicrobial resistance genes, and seven of them contained possibly recombinant DNA. The study indicates presence of GMO contamination that emphasizes the need for further monitoring.

Modeling recent positive selection using identity-by-descent segments.

Recent positive selection can result in an excess of long identity-by-descent (IBD) haplotype segments overlapping a locus. The statistical methods that we propose here address three major objectives in studying selective sweeps: scanning for regions of interest, identifying possible sweeping alleles, and estimating a selection coefficient s. First, we implement a selection scan to locate regions with excess IBD rates. Second, we estimate the allele frequency and location of an unknown sweeping allele by aggregating over variants that are more abundant in an inferred outgroup with excess IBD rate versus the rest of the sample. Third, we propose an estimator for the selection coefficient and quantify uncertainty using the parametric bootstrap. Comparing against state-of-the-art methods in extensive simulations, we show that our methods are more precise at estimating s when s≥0.015. We also show that our 95% confidence intervals contain s in nearly 95% of our simulations. We apply these methods to study positive selection in European ancestry samples from the Trans-Omics for Precision Medicine project. We analyze eight loci where IBD rates are more than four standard deviations above the genome-wide median, including LCT where the maximum IBD rate is 35 standard deviations above the genome-wide median. Overall, we present robust and accurate approaches to study recent adaptive evolution without knowing the identity of the causal allele or using time series data.

Beyond victimhood and perpetration: Reconstruction of the ingroup's historical role in eight Eastern and Western European countries under Nazi occupation

AbstractThe Nazi regime's aggressive expansion across Europe during WWII created a landscape of suffering, resistance, and collaboration. How do lay Europeans today reconstruct their ingroup's roles during Nazi occupation, and how do different role representations relate to defensive responses aimed at protecting the ingroup from threat? We tested two theoretical predictions: Following the identity threat prediction, we expected that denying culpability but endorsing morally favorable group representations (e.g., victim‐heroism) would represent an ingroup‐defensive strategy, correlating with other defensive responses, such as victim‐directed negativity or victim‐blaming. Following the identity management prediction, we expected that precisely accepting culpability and acknowledging threatening representations (e.g., willing collaboration with Germans) would form the basis for a defensive stance and thus correlate with defensive intergroup reactions. Analyzing data from nine European samples spanning eight countries (N = 5474), we found support for the identity management prediction in six contexts: Lay representations as willing collaborators were associated with negative collective emotions and correlated with victim‐directed negativity, whereas victim‐hero representations showed no such connections. The remaining three countries revealed a mixture of the two identity accounts. We discuss implications for understanding historical representations and identity protection in groups that were both victims and perpetrators of massive intergroup atrocities.

Causality of multiple serum metabolites on emotional lability: A two-sample Mendelian randomization study

BackgroundEmotional lability (EL)—a transdiagnostic feature characterized by rapid emotional shifts—contributes significantly to functional impairment across psychiatric disorders, such as depression, bipolar disorder, and schizophrenia. Despite its clinical significance, its etiology remains poorly understood, hindering effective screening and interventions. Growing evidence suggests that metabolic alterations may play a crucial role in the pathophysiology of psychiatric disorders. MethodsA comprehensive Mendelian randomization (MR) design incorporated summary-level data from extensive genome-wide association studies (GWAS) on serum metabolites (8299 European participants) and EL (3268 European samples) to investigate causal associations between genetically determined metabolite levels and EL. Assumptions of instrumental variables, heterogeneity, horizontal pleiotropy, and directionality were assessed alongside sensitivity analyses. ResultsOut of 1400 metabolites and ratios analyzed, 30 metabolites demonstrated causal associations with an increased risk of EL based on the inverse-variance weighted method. Sensitivity analyses identified three potential causal metabolites: hydrocinnamate (OR: 1.277, CI: 1.071–1.522, P = 0.0063), which is associated with an increased risk, while glycolithocholate (OR: 0.779, CI: 0.667–0.911, P = 0.0017) and 3β-hydroxy-5-cholenoic acid (OR: 0.857, CI: 0.756–0.971, P = 0.015) are associated with a decreased risk. ConclusionThis MR study supports a causal link between hydrocinnamate, glycolithocholate, and 3β-hydroxy-5-cholenoic acid levels and the incidence of EL, offering potential metabolic biomarkers and therapeutic targets for EL in psychiatric disorders.

Evidence of a developmental shift in the nature attachment representations: a longitudinal taxometric investigation of secure base script knowledge from middle childhood into adolescence

ABSTRACT Prior research suggests that secure base script knowledge is categorically distributed in middle childhood but becomes dimensionally distributed from late adolescence onward, potentially indicating a developmental shift in the nature of secure base script knowledge. Secure base script knowledge may initially be sparse, giving rise to categorical individual differences, while increased relational experiences later in development might contribute to more elaborated secure base script knowledge and dimensional individual differences. However, the cross-sectional nature of prior research limits inferences about developmental changes. To address this, we conducted a three-year, three-wave longitudinal study with a Western European sample transitioning from middle childhood to adolescence. At Wave 1 (n = 599, M age = 10.30), secure base script knowledge was categorically distributed. By Wave 2 (n = 435, M age = 11.30), distribution was ambiguous, and by Wave 3 (n = 370, M age = 12.09), individual differences were dimensional. These results suggest a developmental shift in secure base script knowledge during the transition into adolescence.

An empirical investigation of ethnic-cultural procedural fairness effects and their boundary conditions among three societal groups in South Africa

ABSTRACT Ethnic-cultural procedural fairness refers to the perception that societal actors use fair and unbiased procedures to make decisions vis-à-vis one’s ethnic-cultural group. Prior research using ethnic-cultural minority samples has convincingly shown that such perceptions are associated with a range of desirable outcomes. Yet, this body of evidence has so far limited its scope to European and North American samples. Moreover, more research is needed on the underlying psychological processes. Therefore, the central aim of the present study was to investigate ethnic-cultural procedural fairness effects among three societal groups in South Africa. In Study 1 (N = 326 black South Africans), we observed relationships between ethnic-cultural fairness perceptions and positive institutional and intergroup attitudes. Institutional and social trust respectively mediated these associations. Study 2 (N = 747) replicated these findings among white (n = 595), but not among coloured South Africans (n = 152). Notably, across both studies, we also obtained evidence for moderation. That is, procedural fairness effects on institutional attitudes were significantly smaller among socioeconomically burdened black participants, and procedural fairness effects on intergroup attitudes were fully curbed among white participants who reported high levels of perceived group discrimination. Taken together, our results call for enhanced attention to procedural fairness obstacles outside of typical WEIRD settings.

Abstract C055: Unraveling pancreatic cancer susceptibility at 5p15.33: Functional characterization of a novel VNTR element

Abstract Genome-wide association studies (GWAS) have identified independent signals at 5p15.33 across numerous cancers, with protective alleles for one cancer often conferring risk for another. Many of these associations are thought to act via allele-specific alterations in the cis- regulation of target genes. Transcriptomic analyses in multiple tissue types implicate two plausible target genes: TERT and CLPTM1L. However, the mechanisms linking cancer susceptibility alleles to their presumed target genes, along with the observed antagonistic pleiotropy between different cancers remain elusive. With this in mind, we employed a comprehensive approach, integrating statistical fine-mapping of GWAS summary statistics with massively parallel reporter assays (MPRA) and a densely tiled CRISPRi screen performed across eight cell lines, representative of four distinct cancers associated with 5p15.33 alleles – pancreatic, melanoma, lung, and bladder cancer. Integrative screening identified up to 30 variants across multiple signals in the locus with putative allele-specific transcriptional activity. Furthermore, a variable number tandem repeat (VNTR) in intron 9 of CLPTM1L emerged as a potent transcriptional enhancer in CRISPRi screening. Leveraging PacBio sequencing, VNTR alleles of European ancestry samples from the 1000 Genomes Project were genotyped and found to be highly polymorphic, with longer VNTRs linked to the haplotype tagged by rs31490-A (risk increasing for pancreatic cancer). Subsequent imputation into a pancreatic cancer GWAS of 9,040 cases and 12,496 controls revealed an association between longer VNTRs and risk of pancreatic cancer (OR for VNTR in the 75th percentile = 1.17, 95% CI = 1.13-1.22, P = 2.21x10-12). The significance of the association for the lead SNP rs31490 after conditioning on the VNTR genotype dropped to P= 2.20x10-5, suggesting that VNTR alleles merit consideration as part of the credible variant set for pancreatic cancer. Targeted CRISPRi assays suggested VNTR-mediated cis-regulation of both TERT and CLPTM1L in PANC-1 and MIA PaCa-2 pancreatic cancer cell lines, while dual luciferase reporter assays in the same cell lines revealed that VNTR enhancer activity is mediated by Hippo pathway transcription factors. In ongoing experiments, we aim to expand on luciferase reporter assays and DNA-protein binding assays in relevant cell lines with the aim of not only deciphering how longer VNTRs differentially exert their transcriptional effects compared to shorter alleles but also characterizing the divergent directions of effect between different cancer types. These findings underscore the proposition that pancreatic cancer susceptibility at the 5p15.33 locus may be mediated by both SNPs and an uncharted class of variants, yet to be characterized in the post-GWAS landscape. Citation Format: Aidan O'Brien, Hyunkyung Kong, Minal Patel, Katelyn E Connelly, Mai Xu, Irene Collins, Jun Zhong, Jason Hoskins, Michelle Ho, Brenen Papenburg, Mark M Iles, Matthew H Law, Maria-Teresa Landi, Rachael Stolzenber- Solomon, Brian M Wolpin, Alison P Klein, Nick Orr, Stephen J Chanock, Sara Lindström, Marc-Henri Stern, Ludmila Prokunina-Olsson, Jieyon Choi, Kevin M Brown, Laufey T Amundadottir. Unraveling pancreatic cancer susceptibility at 5p15.33: Functional characterization of a novel VNTR element [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C055.

A - 77 A Systematic Review of Current Diversity Representation in Neuropsychological Research

Abstract Objective This study investigated current representation of diverse samples in research published in four leading neuropsychology journals. Methods We reviewed 367 articles published in 2023 from Archives of Clinical Neuropsychology, Neuropsychology, Journal of the International Neuropsychological Society, and The Clinical Neuropsychologist. 34 review articles and 4 editorial/announcements were excluded leaving 321 articles coded for age, education, gender/sex, race/ethnicity, and sample country. Results Overall, 89.41% of studies reported gender/sex and 50.46% reported race/ethnicity. Out of 63 original articles that included European populations (e.g., France, Sweden, Denmark, etc.), 93.65% reported gender/sex and 12.7% reported race/ethnicity. Out of 172 original articles that included United States (U.S.) samples, 95.93% reported gender/sex and 80.23% reported race/ethnicity. Studies of U.S. samples reported the following average sociodemographic variables: education 14.94 years (SD = 3.72), age 50.32 years (SD = 21.39), gender/sex 48.09% female and 51.90% male, and race/ethnicity was 65.11% White, 6.64% Black/African American, 2.18% Asian, 1.06% American Indian/Alaskan Native, 0.43% Native Hawaiian/Pacific Islander, and 24.57% unknown/other/mixed race. Additionally, 9.82% of participants were Hispanic/Latino. Conclusions Roughly half of studies did not report on race/ethnicity and this was particularly notable for European samples with more homogeneous populations. Studies with U.S. samples had equitable gender/sex representation but participants were predominantly White and older middle aged. Inconsistencies in how studies stratified race/ethnicity resulted in a large percentage of individuals being classified as unknown/other/mixed. This review highlights the need for more diverse representation in neuropsychological research as Hispanic/Latino, Black/African American, and Asian groups were represented at half their actual numbers in the U.S. population (18.5%, 12.2%, and 5.9% respectively).

Tracking anthropometric dimensions and grip strength among children, adolescents and adults in an indigenous community of southern Mexico: 1968-1978-2000.

To track body size and proportions, arm dimensions and grip strength in children, adolescents, and adults resident in an indigenous community in Oaxaca who were measured on two or three occasions across surveys in 1968, 1978, and 2000. The three cross-sectional surveys included measures of height, weight, sitting height, arm circumference, triceps skinfold, and grip strength in surveys of schoolchildren in 1968 and of schoolchildren, adolescents and adults in 1978 and 2000. Cross-checks of surnames, forenames and ages/dates of birth of participants in the three surveys identified three samples of individuals measured on two occasions (1968-1978, two age groups in 1978-2000) and a subsample of individuals measured in the three surveys. Partial correlations controlling for age at each observation were calculated for each variable in the three sex-specific samples measured on two occasions, and for the subsamples of males and females measured on three occasions. Allowing for variation in age among subsamples, inter-age correlations were moderate to high for stature, moderate for sitting height and estimated leg length, and low to moderate for weight, BMI, arm and estimated arm muscle circumference, triceps skinfold, and grip strength. Allowing for the relatively broad chronological age intervals, the inter-age correlations for height, weight and BMI were at the low end, while those for grip strength and for strength per unit body weight for males (though not females) were generally in the range of correlations noted in studies of European samples. Likely associated with improved health, nutritional, and sanitation conditions, obesity and overweight were emerging among adults by 2000. Obesity and overweight in adults paralleled the introduction of mechanized agriculture that reduced routine physical work. Among children, the association of obesity and overweight is likely with increased nutritional availability, but poor choices in diet.

Causal associations of hypothyroidism with frozen shoulder: a two-sample bidirectional Mendelian randomization study

BackgroundMany studies have investigated the association between hypothyroidism and frozen shoulder, but their findings have been inconsistent. Furthermore, earlier research has been primarily observational, which may introduce bias and does not establish a cause-and-effect relationship. To ascertain the causal association, we performed a two-sample bidirectional Mendelian randomization (MR) analysis.MethodsWe obtained data on “Hypothyroidism” and “Frozen Shoulder” from Summary-level Genome-Wide Association Studies (GWAS) datasets that have been published. The information came from European population samples. The primary analysis utilized the inverse-variance weighted (IVW) method. Additionally, a sensitivity analysis was conducted to assess the robustness of the results.ResultsWe ultimately chose 39 SNPs as IVs for the final analysis. The results of the two MR methods we utilized in the investigation indicated that a possible causal relationship between hypothyroidism and frozen shoulder. The most significant analytical outcome demonstrated an odds ratio (OR) of 1.0577 (95% Confidence Interval (CI):1.0057–1.1123), P = 0.029, using the IVW approach. Furthermore, using the MR Egger method as a supplementary analytical outcome showed an OR of 1.1608 (95% CI:1.0318–1.3060), P = 0.017. Furthermore, the results of our sensitivity analysis indicate that there is no heterogeneity or pleiotropy in our MR analysis. In the reverse Mendelian analysis, no causal relationship was found between frozen shoulders and hypothyroidism.ConclusionOur MR analysis suggests that there may be a causal relationship between hypothyroidism and frozen shoulder.

An atlas of genetic effects on cellular composition of the tumor microenvironment.

Deciphering the composition of the tumor microenvironment (TME) is critical for understanding tumorigenesis and to design immunotherapies. In the present study, we mapped genetic effects on cell-type proportions using single-cell and bulk RNA sequencing data, identifying 3,494 immunity quantitative trait loci (immunQTLs) across 23 cancer types from The Cancer Genome Atlas. Functional annotation revealed regulatory potential and we further assigned 1,668 genes that regulate TME composition. We constructed a combined immunQTL map by integrating data from European and Chinese colorectal cancer (CRC) samples. A polygenic risk score that incorporates these immunQTLs and hits on a genome-wide association study outperformed in CRC risk stratification within 447,495 multiethnic individuals. Using large-scale population cohorts, we identified that the immunQTL rs1360948 is associated with CRC risk and prognosis. Mechanistically, the rs1360948-G-allele increases CCL2 expression, recruiting regulatory T cells that can exert immunosuppressive effects on CRC progression. Blocking the CCL2-CCR2 axis enhanced anti-programmed cell death protein 1 ligand therapy. Finally, we have established a database (CancerlmmunityQTL2) to serve the research community and advance our understanding of immunogenomic interactions in cancer pathogenesis.

Bivariate genome-wide association study of circulating fibrinogen and C-reactive protein levels

BackgroundFibrinogen and C-reactive protein (CRP) play an important role in inflammatory pathways and share multiple genetic loci reported in previously published genome-wide association studies (GWAS), highlighting their common genetic background. Leveraging the shared biology may identify further loci pleiotropically associated with both fibrinogen and CRP. ObjectivesTo identify novel genetic variants that are pleiotropic and associated with both fibrinogen and CRP, by integrating both phenotypes in a bivariate GWAS by using a multitrait GWAS. MethodsWe performed a bivariate GWAS to identify further pleiotropic genetic loci, using summary statistics of previously published GWAS on fibrinogen (n = 120 246) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, consisting of European ancestry samples and CRP (n = 363 228) from UK Biobank, including 5 different population groups. The main analysis was performed using metaUSAT and N-GWAMA. We conducted replication for novel CRP associations to test the robustness of the findings using an independent GWAS for CRP (n = 148 164). We also performed colocalization analysis to compare the associations in identified loci for the 2 traits and Genotype-Tissue Expression data. ResultsWe identified 87 pleiotropic loci that overlapped between metaUSAT and N-GWAMA, including 23 previously known for either fibrinogen or CRP, 58 novel loci for fibrinogen, and 6 novel loci for both fibrinogen and CRP. Overall, there were 30 pleiotropic and novel loci for both traits, and 7 of these showed evidence of colocalization, located in or near ZZZ3, NR1I2, RP11-72L22.1, MICU1, ARL14EP, SOCS2, and PGM5. Among these 30 loci, 13 replicated for CRP in an independent CRP GWAS. ConclusionBivariate GWAS identified additional associated loci for fibrinogen and CRP. This analysis suggests fibrinogen and CRP share a common genetic architecture with many pleiotropic loci.

Factors affecting adherence to recommendations on pre-operative cardiac testing: A cohort study.

Cardiac risk evaluation prior to noncardiac surgery is fundamental to tailor peri-operative management to patient's estimated risk. Data on the degree of adherence to guidelines in patients at cardiovascular risk in Europe and factors influencing adherence are underexplored. The aim of this analysis was to describe the degree of adherence to [2014 European Society of Cardiology (ESC)/European Society of Anaesthesiology (ESA) guidelines] recommendations on rest echocardiography [transthoracic echocardiography (TTE)] and to stress imaging prior to noncardiac surgery in a large European sample and to assess factors potentially affecting adherence. Secondary analysis of a multicentre, international, prospective cohort study (MET-REPAIR). Twenty-five European centres of all levels of care that enrolled patients between 2017 and 2020. With elevated cardiovascular risk undergoing in-hospital elective, noncardiac surgery. (Non)adherence to each pre-operative TTE and stress imaging recommendations classified as guideline-adherent, overuse and underuse. We performed descriptive analysis. To explore the impact of patients' sex, age, geographical region, and hospital teaching status, we conducted multivariate multinominal regression analysis. Out of 15 983 patients, 15 529 were analysed (61% men, mean age 72 ± 8 years). Overuse (conduction in spite of class III) and underuse (nonconduction in spite of class I recommendation) for pre-operative TTE amounted to 16.6% (2542/15 344) and 6.6% (1015/15 344), respectively. Stress imaging overuse and underuse amounted to 1.7% (241/14 202) and 0.4% (52/14 202) respectively. Male sex, some age categories and some geographical regions were significantly associated with TTE overuse. Male sex and some regions were also associated with TTE underuse. Age and regions were associated with overuse of stress imaging. Male sex, age, and some regions were associated with stress imaging underuse. Adherence to pre-operative stress imaging recommendation was high. In contrast, adherence to TTE recommendations was moderate. Both patients' and geographical factors affected adherence to joint ESC/ESA guidelines. NCT03016936.

Gestational DNA methylation age as a marker for fetal development and birth outcomes: findings from the Boston Birth Cohort

BackgroundGestational DNA methylation age (GAmAge) has been developed and validated in European ancestry samples. Its applicability to other ethnicities and associations with fetal stress and newborn phenotypes such as inflammation markers are still to be determined. This study aims to examine the applicability of GAmAge developed from cord blood samples of European decedents to a racially diverse birth cohort, and associations with newborn phenotypes.MethodsGAmAge based on 176 CpGs (Haftorn GAmAge) was calculated for 940 children from a US predominantly urban, low-income, multiethnic birth cohort. Cord blood DNA methylation was profiled by Illumina EPIC array. Newborn phenotypes included anthropometric measurements and, for a subset of newborns (N = 194), twenty-seven cord blood inflammatory markers (sandwich immunoassays).ResultsGAmAge had a stronger correlation with GEAA in boys (r = 0.89, 95% confidence interval (CI) [0.87,0.91]) compared with girls (r = 0.83, 95% CI [0.80,0.86]), and was stronger among extremely preterm to very preterm babies (r = 0.91, 95% CI [0.81,0.96]), compared with moderate (r = 0.48, 95% CI [0.34,0.60]) and term babies (r = 0.58, 95% CI [0.53,0.63]). Among White newborns (N = 51), the correlation between GAmAge vs. GEAA was slightly stronger (r = 0.89, 95% CI [0.82,0.94]) compared with Black/African American newborns (N = 668; r = 0.87, 95% CI [0.85,0.89]) or Hispanic (N = 221; r = 0.79, 95% CI [0.74,0.84]). Adjusting for GEAA and sex, GAmAge was associated with anthropometric measurements, cord blood brain-derived neurotrophic factor (BDNF), and monocyte chemoattractant protein-1 (MCP-1) (p < 0.05 for all).ConclusionsGAmAge estimation is robust across different populations and racial/ethnic subgroups. GAmAge may be utilized as a proxy for GEAA and for assessing fetus development, indicated by inflammatory state and birth outcomes.

Assessing the causal relationship between metabolic biomarkers and coronary artery disease by Mendelian randomization studies

The development of coronary artery disease (CAD) is significantly affected by impaired endocrine and metabolic status. Under this circumstance, improved prevention and treatment of CAD may result from knowing the connection between metabolites and CAD. This study aims to delve into the causal relationship between human metabolic biomarkers and CAD by using two-sample Mendelian randomization (MR). Utilizing two-sample bidirectional MR analysis, we assessed the correlation between 1400 blood metabolites and CAD, and the metabolites data from the CLSA, encompassing 8299 participants. Metabolite analysis identified 1091 plasma metabolites and 309 ratios as instrumental variables. To evaluate the causal link between metabolites and CAD, we analyzed three datasets: ebi-a-GCST005195 (547,261 European & East Asian samples), bbj-a-159 (29,319 East Asian CAD cases & 183,134 East Asian controls), and ebi-a-GCST005194 (296,525 European & East Asian samples). To estimate causal links, we utilized the IVW method. To conduct sensitivity analysis, we used MR-Egger, Weighted Median, and MR-PRESSO. Additionally, we employed MR-Egger interception and Cochran’s Q statistic to assess potential heterogeneity and pleiotropy. What’s more, replication and reverse analyses were performed to verify the reliability of the results and the causal order between metabolites and disease. Furthermore, we conducted a pathway analysis to identify potential metabolic pathways. 59 blood metabolites and 27 metabolite ratios nominally associated with CAD (P < 0.05) were identified by IVW analysis method. A total of four known blood metabolites, namely beta-hydroxyisovaleroylcarnitine (OR 1.06, 95% CI 1.027–1.094, FDR 0.07), 1-palmitoyl-2-arachidonoyl (OR 1.07, 95% CI 1.029–1.110, FDR 0.09), 1-stearoyl-2- docosahexaenoyl (OR 1.07, 95% CI 1.034–1.113, FDR 0.07) and Linoleoyl-arachidonoyl-glycerol, (OR 1.07, 95% CI 1.036–1.105, FDR 0.05), and two metabolite ratios, namely spermidine to N-acetylputrescine ratio (OR 0.94, 95% CI 0.903–0.972, FDR 0.09) and benzoate to linoleoyl-arachidonoyl-glycerol ratio (OR 0.87, 95% CI 0.879–0.962, FDR 0.07), were confirmed as having a significant causal relationship with CAD, after correcting for the FDR method (p < 0. 1). A causal relationship was found to be established between beta -hydroxyisovalerylcarnitine and CAD with the validation in other two datasets. Moreover, multiple metabolic pathways were discovered to be associated with CAD. Our study supports the hypothesis that metabolites have an impact on CAD by demonstrating a causal relationship between human metabolites and CAD. This study is important for new strategies for the prevention and treatment of CAD.

Association of the rs1042522 SNP with prostate cancer risk: a study of cancer tissues, primary tumor cultures, and serum samples from a Spanish Caucasian population.

Prostate cancer (PCa) is a leading cause of cancer-related deaths in European men, emphasizing the urgent need for effective risk assessment strategies. The TP53 gene, a tumor suppressor gene frequently mutated in cancer, commonly harbors the rs1042522 single nucleotide polymorphism (SNP), known as the P72R SNP, which may influence PCa susceptibility. This study investigated the prevalence of the P72R SNP in European Caucasian PCa samples and its association with PCa risk. Genotyping was conducted on 12 hormone-naïve aggressive PCa cultures (hnPCs) from untreated patients (Gleason ≥8), 11 radical prostatectomies (RP), and 94 serum samples using DNA Sanger sequencing and melting curve analysis. Comparative analysis utilized data from the GnomAD database's European Caucasian non-cancer population. Our results demonstrate a significantly higher frequency of the P72R SNP in PCa samples and serums compared to the general European non-cancer population. A robust and statistically significant association (p < 0.0001) between the SNP and prostate cancer risk was identified, with an odds ratio of 7.937 (95% CI 5.37-11.00). Notably, the G allele (R72) showed a pronounced prevalence in high Gleason score (≥8) patients, although statistical significance was not reached. These results highlight a potential association with undifferentiated and malignant PCa lesions. The compelling association between the P72R SNP and prostate cancer risk underscores the potential utility of this marker for the early identification of patients at risk of aggressive metastatic prostate cancer. This insight could empower further research to intervene at an early stage by offering enhanced opportunities for timely and targeted interventions.