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Background: The emerging use of biomarkers in research and tailored care introduces a need for information about the association between biomarkers and basic demographics and lifestyle factors revealing expectable concentrations in healthy individuals while considering general demographic differences., Methods: A selection of 47 biomarkers, including markers of inflammation and vascular stress, were measured in plasma samples from 9876 Danish Blood Donor Study participants. Using regression models, we examined the association between biomarkers and sex, age, Body Mass Index (BMI), and smoking., Results: Here we show that concentrations of inflammation and vascular stress biomarkers generally increase with higher age, BMI, and smoking. Sex-specific effects are observed for multiple biomarkers., Conclusion: This study provides comprehensive information on concentrations of 47 plasma biomarkers in healthy individuals. The study emphasizes that knowledge about biomarker concentrations in healthy individuals is critical for improved understanding of disease pathology and for tailored care and decision support tools., (© 2024. The Author(s).)

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785., (© 2023. The Author(s).)

Aims: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS., Methods and Results: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS., Conclusion: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies., Competing Interests: Conflict of interest Scott M. Damrauer receives research support (to the University of Pennsylvania) from RenalytixAI and personal fees from Caico Ibs, both outside the scope of the present work. SMD is also named as a co-inventor on a government-owned US Patent application related to the use of genetic risk prediction for venous thromboembolic disease filed by the US Department of Veterans Affairs in accordance with Federal regulatory requirements. SMD is named as a co-inventor on a Government-owned US Patent application related to the use of PDE3B inhibition for preventing cardiovascular disease filed by the US Department of Veterans Affairs in accordance with Federal regulatory requirements. Stefan Söderberg has received speaker honoraria and consulting fees from Actelion Ltd. George Thanassoulis has received consulting fees from Ionis Pharmaceuticals and has participated in advisory boards for Amgen, Sanofi, Novartis, HLS Therapeutics and Silence. Morten Salling Olesen has received 5.000.000 dkrfra Sundhedsdonationer.Journalnr. 2022-0243. David O. Arnar has received travel support from Pfizer to attend the ESC 2022 Scientific Meeting in Barcelona and has stock options in Sidekick Health Digital Therapeutics. Henning Bundgaard has received lecture fees from Amgen, MSD, Sanofi-Avensis, BMS and grants from NordForsk, Innovation Fond, Denmark, The Capital Regions Research Foundation. Alex Hoerby Christensen—Novo Nordisk Foundation NNF20OC0065799. Romaine Capoulade has received an Honorarium for one lecture from Novartis. Robert Clarke has received support from BAYER (China Kadoorie Biobank). Unnur Thorsteinsdottir’s research is funded by deCODE genetics/Amgen. Daniel F. Gudbjartsson receives funds from deCODE Genetics/Amgen. Until 1 June 2022, Gudmundur Thorgeirsson was a part time employee of deCode Genetics that is owned by Amgen. Hilma Holm is an employee of deCODE genetics/Amgen Inc. Anna Helgadottir is an employee of deCODE genetics/Amgen Inc., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Syncope is a common and clinically challenging condition. In this study, the genetics of syncope were investigated to seek knowledge about its pathophysiology and prognostic implications., Methods and Results: This genome-wide association meta-analysis included 56 071 syncope cases and 890 790 controls from deCODE genetics (Iceland), UK Biobank (United Kingdom), and Copenhagen Hospital Biobank Cardiovascular Study/Danish Blood Donor Study (Denmark), with a follow-up assessment of variants in 22 412 cases and 286 003 controls from Intermountain (Utah, USA) and FinnGen (Finland). The study yielded 18 independent syncope variants, 17 of which were novel. One of the variants, p.Ser140Thr in PTPRN2, affected syncope only when maternally inherited. Another variant associated with a vasovagal reaction during blood donation and five others with heart rate and/or blood pressure regulation, with variable directions of effects. None of the 18 associations could be attributed to cardiovascular or other disorders. Annotation with regard to regulatory elements indicated that the syncope variants were preferentially located in neural-specific regulatory regions. Mendelian randomization analysis supported a causal effect of coronary artery disease on syncope. A polygenic score (PGS) for syncope captured genetic correlation with cardiovascular disorders, diabetes, depression, and shortened lifespan. However, a score based solely on the 18 syncope variants performed similarly to the PGS in detecting syncope risk but did not associate with other disorders., Conclusion: The results demonstrate that syncope has a distinct genetic architecture that implicates neural regulatory processes and a complex relationship with heart rate and blood pressure regulation. A shared genetic background with poor cardiovascular health was observed, supporting the importance of a thorough assessment of individuals presenting with syncope., Competing Interests: Conflicts of interest: The following authors are employees of deCODE genetics/Amgen, Inc.: Hildur M Aegisdottir, Rosa B Thorolfsdottir, Gardar Sveinbjornsson, Olafur A Stefansson, Bjarni Gunnarsson, Vinicius Tragante, Lilja Stefansdottir, Thorgeir E Thorgeirsson, Egil Ferkingstad, Gudmar Thorleifsson, Michael L Frigge, Kristjan E Hjorleifsson, Erna V Ivarsdottir, Anna Helgadottir, Solveig Gretarsdottir, Valgerdur Steinthorsdottir, Asmundur Oddsson, Hannes P Eggertsson, Gisli H Halldorsson, Patrick Sulem, Gudmundur Norddahl, Gudrun Rutsdottir, Gudmundur Thorgeirsson, David O Arnar, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, Hilma Holm, and Kari Stefansson. Karina Banasik and Søren Brunak acknowledge the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10 -24 , OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in bilateral/recurrent/persistent cases than nonrecurrent/nonpersistent cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS., (© 2022. The Author(s).)