Publications by authors named "Marcel den Hoed"

Background And Aims: Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date.

View Article and Find Full Text PDF

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for NAFLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using NAFLD surrogate phenotypes have been used, but only a small number of loci have been identified to date.

View Article and Find Full Text PDF

Background: Whether obesity is a cause or consequence of low physical activity levels and more sedentary time has not yet been fully elucidated. Better instrumental variables and a more thorough consideration of potential confounding variables that may influence the causal inference between physical activity and obesity are needed.

Methods: Leveraging results from our recent genome-wide association study for leisure time moderate-to-vigorous intensity (MV) physical activity and screen time, we here disentangle the causal relationships between physical activity, sedentary behavior, education-defined by years of schooling-and body mass index (BMI), using multiple univariable and multivariable Mendelian Randomization (MR) approaches.

View Article and Find Full Text PDF

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals.

View Article and Find Full Text PDF
Article Synopsis
  • This study examines the relationship between resting heart rate and cardiovascular diseases, identifying 493 genetic variants linked to this trait through a large-scale analysis of 835,465 individuals.
  • It highlights the significance of higher genetically predicted resting heart rates, which are associated with an increased risk of dilated cardiomyopathy but lower risk for conditions like atrial fibrillation and ischemic strokes.
  • The study also challenges previous findings on resting heart rate and all-cause mortality, suggesting earlier results may have been influenced by biases, ultimately enhancing our understanding of the biological implications of resting heart rate in cardiovascular health.
View Article and Find Full Text PDF
Article Synopsis
  • Researchers analyzed genetic data from over 785,000 individuals of European descent to find 43 specific genomic regions related to reproductive success, measured by the number of children and instances of childlessness.
  • These genetic regions influence various factors tied to reproduction, such as puberty onset, age at first birth, and conditions like endometriosis, highlighting complex biological networks at play.
  • The study also uncovered a potential trade-off between higher reproductive output and shortened reproductive lifespan in certain genes, suggesting some genetic traits are linked to ongoing natural selection affecting fertility.
View Article and Find Full Text PDF

Aims/hypothesis: Genome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes risk and related glycaemic traits. However, little is known about the function of the zinc finger transcription factor Ras-responsive element binding protein 1 (RREB1) in glucose homeostasis or how changes in its expression and/or function influence diabetes risk.

Methods: A zebrafish model lacking rreb1a and rreb1b was used to study the effect of RREB1 loss in vivo.

View Article and Find Full Text PDF
Article Synopsis
  • - The study analyzed data from 703,901 individuals and identified 99 genetic loci related to physical activity levels and sedentary behavior, particularly focusing on leisure time activities and screen use.
  • - Certain genes linked to sedentary behavior show heightened expression in skeletal muscle when influenced by resistance training, highlighting a connection between genetics and exercise.
  • - The findings suggest that lower screen time and increased physical activity can positively impact health, but these effects may be influenced by factors like body mass index (BMI).
View Article and Find Full Text PDF
Article Synopsis
  • CRISPR-Cas9 shows promise for curing diseases but poses risks of unintended mutations, highlighting the need for safe therapies.
  • * In a study involving zebrafish, researchers discovered that editing can lead to structural variants (insertions and deletions) in about 6% of modified larvae, with these mutations observed in both targeted and non-targeted DNA regions.
  • * The findings emphasize the importance of testing for off-target mutations before using CRISPR-Cas9 in patients, as a significant percentage of zebrafish offspring inherited these unintended changes.
View Article and Find Full Text PDF

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965.

View Article and Find Full Text PDF
Article Synopsis
  • Obesity is a significant risk factor for diseases related to heart and metabolism, but some people with obesity don’t develop these health issues.
  • Researchers have found 62 genetic loci where the same genetic variant is linked to both increased body fat and a lower risk of cardiometabolic diseases, suggesting complex interactions between genetics and health outcomes.
  • The study highlights key genes involved in fat distribution, adipocyte (fat cell) function, insulin signaling, energy expenditure, tissue "browning," and inflammation, indicating potential targets for treatments aimed at reducing disease risk associated with obesity.
View Article and Find Full Text PDF

Background: One ongoing concern about CRISPR-Cas9 genome editing is that unspecific guide RNA (gRNA) binding may induce off-target mutations. However, accurate prediction of CRISPR-Cas9 off-target activity is challenging. Here, we present SMRT-OTS and Nano-OTS, two novel, amplification-free, long-read sequencing protocols for detection of gRNA-driven digestion of genomic DNA by Cas9 in vitro.

View Article and Find Full Text PDF

A meta-analysis of genome-wide association studies (GWAS) identified eight loci that are associated with heart rate variability (HRV), but candidate genes in these loci remain uncharacterized. We developed an image- and CRISPR/Cas9-based pipeline to systematically characterize candidate genes for HRV in live zebrafish embryos. Nine zebrafish orthologues of six human candidate genes were targeted simultaneously in eggs from fish that transgenically express GFP on smooth muscle cells (Tg[acta2:GFP]), to visualize the beating heart.

View Article and Find Full Text PDF
Article Synopsis
  • An amendment to the original paper has been released.
  • This update includes important changes or corrections to the content.
  • Readers can find the link to access the amendment conveniently located at the top of the paper.
View Article and Find Full Text PDF

This study aimed to analyze the intra-individual variation in VO of human subjects using total-capture and free-flow indirect calorimetry. Twenty-seven men (27 ± 5 year; VO 49-79 mL•kg •min ) performed two maximal exertion tests (CPETs) on a cycle ergometer, separated by a 7 ± 2 day interval. VO and VCO were assessed using an indirect calorimeter (Omnical) with total capture of exhalation in a free-flow airstream.

View Article and Find Full Text PDF

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity.

View Article and Find Full Text PDF

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression.

View Article and Find Full Text PDF

Background: The etiology of childhood cancer is not well understood, but may be linked to prenatal and perinatal factors, such as maternal diabetes. However, this association has not been examined in depth. We aimed to determine if maternal diabetes is associated with risk of childhood brain tumor (CBT), leukemia (all types combined and acute lymphoblastic leukemia [ALL] separately), and lymphoma.

View Article and Find Full Text PDF

Purpose: Physical activity unquestionably maintains and improves health; however, physical activity levels globally are low and not rising despite all the resources devoted to this goal. Attention in both the research literature and the public policy domain has focused on social-behavioral factors; however, a growing body of literature suggests that biological determinants play a significant role in regulating physical activity levels. For instance, physical activity level, measured in various manners, has a genetic component in both humans and nonhuman animal models.

View Article and Find Full Text PDF

Background And Aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels.

View Article and Find Full Text PDF

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4).

View Article and Find Full Text PDF

A PHP Error was encountered

Severity: Notice

Message: fwrite(): Write of 34 bytes failed with errno=28 No space left on device

Filename: drivers/Session_files_driver.php

Line Number: 272

Backtrace:

A PHP Error was encountered

Severity: Warning

Message: session_write_close(): Failed to write session data using user defined save handler. (session.save_path: /var/lib/php/sessions)

Filename: Unknown

Line Number: 0

Backtrace: