Abstract Background An updated definition was developed to better evaluate cardiovascular health (CVH). We aimed to investigate whether optimal or improvement of six CVH metrics defined by new Life's Essential 8 (LE8) may counteract the risk of subclinical atherosclerosis among patients with hyperglycemia. Methods We conducted a prospective analysis of 5225 participants without prior cardiovascular diseases, of whom 4768 had complete data on CVH change. Subjects with CVH scores of 0–49, 50–79, and 80–100 points were categorized as having low, moderate, or high CVH, respectively. Subclinical atherosclerosis was evaluated by brachial‐ankle pulse wave velocity, pulse pressure and albuminuria, both separately and in combination. Results Of the 5225 participants, 1937 (37.1%) had normal glucose regulation, while 3288 (62.9%) had hyperglycemia. The multivariable‐adjusted odds ratio (OR) for composite subclinical atherosclerosis was 2.34 (95% confidence interval [CI], 1.88–2.91), 1.43 (95% CI, 1.21–1.70), and 0.74 (95% CI, 0.46–1.18), for participants with hyperglycemia who had low, moderate, or high overall CVH scores, respectively, compared with participants with normal glucose regulation. In addition, compared with those with stable CVH and normal glucose regulation, participants who exhibited greater improvements in overall CVH from 2010 to 2014 had a reduced risk of composite subclinical atherosclerosis with an OR of 0.72 (95% CI, 0.53–0.98) for those with normal glucose regulation, and 1.13 (95% CI, 0.87–1.48) for those with hyperglycemia. Conclusions The novel defined CVH using six metrics was inversely associated with subsequent risk of subclinical atherosclerosis. Both the status of CVH and its changes modified the relationship between hyperglycemia and subclinical atherosclerosis. image
Abstract Psychiatric disorders are the leading cause of disability worldwide while the pathogenesis remains unclear. Genome-wide association studies (GWASs) have made great achievements in detecting disease-related genetic variants. However, functional information on the underlying biological processes is often lacking. Current reports propose the use of metabolic traits as functional intermediate phenotypes (the so-called genetically determined metabotypes or GDMs) to reveal the biological mechanisms of genetics in human diseases. Here we conducted a two-sample Mendelian randomization analysis that uses GDMs to assess the causal effects of 486 human serum metabolites on 5 major psychiatric disorders, which respectively were schizophrenia (SCZ), major depression (MDD), bipolar disorder (BIP), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). Using genetic variants as proxies, our study has identified 137 metabolites linked to the risk of psychiatric disorders, including 2-methoxyacetaminophen sulfate, which affects SCZ (P = 1.7 × 10–5) and 1-docosahexaenoylglycerophosphocholine, which affects ADHD (P = 5.6 × 10–5). Fourteen significant metabolic pathways involved in the 5 psychiatric disorders assessed were also detected, such as glycine, serine, and threonine metabolism for SCZ (P = .0238), Aminoacyl-tRNA biosynthesis for both MDD (P = .0144) and ADHD (P = .0029). Our study provided novel insights into integrating metabolomics with genomics in order to understand the mechanisms underlying the pathogenesis of human diseases.
Abstract Large studies such as UK Biobank are increasingly used for GWAS and Mendelian randomization (MR) studies. However, selection into and dropout from studies may bias genetic and phenotypic associations. We examine genetic factors affecting participation in four optional components in up to 451,306 UK Biobank participants. We used GWAS to identify genetic variants associated with participation, MR to estimate effects of phenotypes on participation, and genetic correlations to compare participation bias across different studies. 32 variants were associated with participation in one of the optional components ( P < 6 × 10 −9 ), including loci with links to intelligence and Alzheimer’s disease. Genetic correlations demonstrated that participation bias was common across studies. MR showed that longer educational duration, older menarche and taller stature increased participation, whilst higher levels of adiposity, dyslipidaemia, neuroticism, Alzheimer’s and schizophrenia reduced participation. Our effect estimates can be used for sensitivity analysis to account for selective participation biases in genetic or non-genetic analyses.
Abstract Trace elements are important for human health but may exert toxic or adverse effects. Mechanisms of uptake, distribution, metabolism, and excretion are partly under genetic control but have not yet been extensively mapped. Here we report a comprehensive multi-element genome-wide association study (GWAS) of 57 essential and non-essential trace elements. We performed GWA meta-analyses of 14 trace elements in up to 6580 Scandinavian whole-blood samples, and GWASs of 43 trace elements in up to 2819 samples measured only in the Trøndelag Health Study (HUNT). We identified 11 novel genetic loci associated with blood concentrations of arsenic, cadmium, manganese, selenium, and zinc in genome-wide meta-analyses. In HUNT, several genome-wide significant loci were also indicated for other trace elements. Using two-sample Mendelian randomization, we found several indications of weak to moderate effects on health outcomes, the most precise being a weak harmful effect of increased zinc on prostate cancer. However, independent validation is needed. Our new understanding of trace element-associated genetic variants may help establish consequences of trace elements on human health.
Abstract Background Rho GTPases are a family of 20 intracellular signalling proteins that influence cytoskeletal dynamics, cell migration and cell cycle progression. Rho GTPases are implicated in breast cancer progression but their role in breast cancer aetiology is unknown. As aberrant Rho GTPase activity could be associated with breast cancer, we aimed to determine the potential for a causal role of Rho GTPase gene expression in breast cancer risk, using two-sample Mendelian randomization (MR). Methods MR was undertaken in 122,977 breast cancer cases and 105,974 controls, including 69,501 estrogen receptor positive (ER+) cases and 105,974 controls, and 21,468 ER negative (ER-) cases and 105,974 controls. Single nucleotide polymorphisms (SNPs) underlying expression quantitative trait loci (eQTLs) obtained from normal breast tissue, breast cancer tissue and blood were used as genetic instruments for Rho GTPase expression. Colocalisation was performed as a sensitivity analysis to examine whether findings reflected shared causal variants or genomic confounding. Results We identified genetic instruments for 14 of the 20 human Rho GTPases. Using eQTLs obtained from normal breast tissue and normal blood, we identified evidence of a causal role of RHOD in overall and ER+ breast cancers (overall breast cancer: odds ratio (OR) per standard deviation (SD) increase in expression level 1.06; (95% confidence interval (CI): 1.03, 1.09; P=5.65×10-5) and OR 1.22 (95% CI: 1.11, 1.35; P=5.22×10 −5 ) in normal breast tissue and blood respectively). The direction of association was consistent for ER- breast cancer, although the effect-estimate was imprecisely estimated. Using eQTLs from breast cancer tissue and normal blood there was some evidence that CDC42 was inversely associated with overall and ER+ breast cancer risk. The evidence from colocalization analyses strongly supported the MR results particularly for RHOD . Conclusions Our study suggests a potential causal role of increased RHOD gene expression, and a potential protective role for CDC42 gene expression, in overall and ER+ breast cancers. These finding warrant validation in independent samples and further biological investigation to assess whether they may be suitable targets for drug targeting.
Additional file 1. Table S1. Study genetic processing steps with relevant numbers. Table S2. Eigenvalue and eigenvector for each continental ancestry group. Table S3. United Nations geoscheme for each country and continent present in the study.
Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk.
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