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AimsWhile most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation.Methods and resultsWe carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro.ConclusionsA large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

Simple Summary: In the last few decades, studies have found many common genetic variants linked to breast cancer. Most of these variants are in non-coding regions or regions that do not directly affect gene function. This study aims to see if a polygenic risk score (PRS) based on functional variants could better predict breast cancer risk compared to an established 313-variant breast cancer PRS. Using publicly available summary data from GWASs, and Quantitative Trait Locus studies of gene expression and DNA methylation, we identified 149 variants potentially causally linked to the risk of developing breast cancer; the weighted sum of these variants was designated as the functional variant. The functional PRS was less effective at predicting breast cancer than the established PRS in 3560 breast cancer patients and 3383 non-breast cancer individuals. Combining both scores did not substantially enhance the prediction accuracy of the established PRS. Purpose: To assess the association of a polygenic risk score (PRS) for functional genetic variants with the risk of developing breast cancer. Methods: Summary data-based Mendelian randomization (SMR) and heterogeneity in dependent instruments (HEIDI) were used to identify breast cancer risk variants associated with gene expression and DNA methylation levels. A new SMR-based PRS was computed from the identified variants (functional PRS) and compared to an established 313-variant breast cancer PRS (GWAS PRS). The two scores were evaluated in 3560 breast cancer cases and 3383 non-cancer controls and also in a prospective study (n = 10,213) comprising 418 cases. Results: We identified 149 variants showing pleiotropic association with breast cancer risk (eQTLHEIDI > 0.05 = 9, mQTLHEIDI > 0.05 = 165). The discriminatory ability of the functional PRS (AUCcontinuous [95% CI]: 0.540 [0.526 to 0.553]) was found to be lower than that of the GWAS PRS (AUCcontinuous [95% CI]: 0.609 [0.596 to 0.622]). Even when utilizing 457 distinct variants from both the functional and GWAS PRS, the combined discriminatory performance remained below that of the GWAS PRS (AUCcontinuous, combined [95% CI]: 0.561 [0.548 to 0.575]). A binary high/low-risk classification based on the 80th centile PRS in controls revealed a 6% increase in cases using the GWAS PRS compared to the functional PRS. The functional PRS identified an additional 12% of high-risk cases but also led to a 13% increase in high-risk classification among controls. Similar findings were observed in the SCHS prospective cohort, where the GWAS PRS outperformed the functional PRS, and the highest-performing PRS, a combined model, did not significantly improve over the GWAS PRS. Conclusions: While this study identified potentially functional variants associated with breast cancer risk, their inclusion did not substantially enhance the predictive accuracy of the GWAS PRS. [ABSTRACT FROM AUTHOR]

Background Mendelian randomization (MR) studies are susceptible to metadata errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control (QC) pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can be used to identify and correct for such errors. Methods We collated summary association statistics from fatty acid and cancer genome-wide association studies (GWAS) and subjected the collated data to a comprehensive QC pipeline. We identified metadata errors through comparison of study-specific statistics to external reference data sets (the National Human Genome Research Institute-European Bioinformatics Institute GWAS catalogue and 1000 genome super populations) and other analytical issues through comparison of reported to expected genetic effect sizes. Comparisons were based on three sets of genetic variants: (i) GWAS hits for fatty acids, (ii) GWAS hits for cancer and (iii) a 1000 genomes reference set. Results We collated summary data from 6 fatty acid and 54 cancer GWAS. Metadata errors and analytical issues with the potential to introduce substantial bias were identified in seven studies (11.6%). After resolving metadata errors and analytical issues, we created a data set of 219 842 genetic associations with 90 cancer types, generated in analyses of 566 665 cancer cases and 1 622 374 controls. Conclusions In this large MR collaboration, 11.6% of included studies were affected by a substantial metadata error or analytical issue. By increasing the integrity of collated summary data prior to their analysis, our protocol can be used to increase the reliability of downstream MR analyses. Our pipeline is available to other researchers via the CheckSumStats package (https://github.com/MRCIEU/CheckSumStats). [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to assess if single nucleotide polymorphisms (SNPs) in lung mucins MUC5B and MUC5AC are associated with Mycobacterium tuberculosis outcomes. Methods Independent SNPs in MUC5B and MUC5AC (genotyped by Illumina HumanOmniExpress array) were assessed for associations with tumor necrosis factor (TNF) concentrations (measured by immunoassay) in cerebral spinal fluid (CSF) from tuberculous meningitis (TBM) patients. SNPs associated with CSF TNF concentrations were carried forward for analyses of pulmonary and meningeal tuberculosis susceptibility and TBM mortality. Results MUC5AC SNP rs28737416 T allele was associated with lower CSF concentrations of TNF (P = 1.8 × 10−8) and IFN-γ (P = 2.3 × 10−6). In an additive genetic model, rs28737416 T/T genotype was associated with higher susceptibility to TBM (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.03–1.49; P =.02), but not pulmonary tuberculosis (OR, 1.11, 95% CI,.98–1.25; P =.10). TBM mortality was higher among participants with the rs28737416 T/T and T/C genotypes (35/119, 30.4%) versus the C/C genotype (11/89, 12.4%; log-rank P =.005) in a Vietnam discovery cohort (n = 210), an independent Vietnam validation cohort (n = 87; 9/87, 19.1% vs 1/20, 2.5%; log-rank P =.02), and an Indonesia validation cohort (n = 468, 127/287, 44.3% vs 65/181, 35.9%; log-rank P =.06). Conclusions MUC5AC variants may contribute to immune changes that influence TBM outcomes. [ABSTRACT FROM AUTHOR]

The spatial and spectral information contained in the hyperspectral image (HSI) make it widely used in many fields. However, the sharp increase of HSI data brings enormous pressure to the data storage and real‐time transmission. The research shows that hyperspectral compressive sensing (HCS) breaks through the bottleneck of the Nyquist sampling theorem, which can relieve the massive pressure on data storage and real‐time transmission. Existing HCS methods try to design advanced compression sampling matrix or reconstruction algorithms, but cannot connect the two through a unified framework. To further improve the image reconstruction quality, a novel codec space‐spectrum joint dense residual network (CDS2‐DResN) is proposed. The CDS2‐DResN is divided into block compression sampling part and reconstruction part. For block compression sampling, coded convolutional layer (CCL) is leveraged to compress and sample HSI. For measurements reconstruction, deconvolution layer is first leveraged to initially reconstruct HSI, and then build a space‐spectrum joint network to refine the initial reconstructed HSI. Moreover, the CCL and reconstruction network are optimized via a unified framework, which can simplify the pre‐processing and post‐processing process of HCS. Extensive experiments have shown that CDS2‐DResN has an excellent HCS reconstruction effect at measurement rates 0.25, 0.10, 0.04 and 0.01, respectively. [ABSTRACT FROM AUTHOR]

Background Understanding the genetic predisposition to cardiovascular disease (CVD) may help to improve clinical intervention strategies. Lifestyle factors, such as diet, may differ among ethnic groups and may, in turn, modify individuals' risks to diseases. Objectives We examined the genetic predisposition to ever smoking in relation to CVD mortality and assessed whether such an association could be modified by dietary intake. Methods A total of 23,760 Chinese adults from the Singapore Chinese Heath Study who were free of cancer and CVD at recruitment (1993–1998) were included in the study. A weighted genetic risk score (wGRS) was calculated to define the genetically determined regular smoking behavior (never or ever). Multivariable-adjusted Cox regression models were used to assess the association between the wGRS and CVD mortality. We also conducted a 1-sample Mendelian randomization analysis for ever smoking and CVD mortality. Results Over a mean of 22.6 years of follow-up, 2301 CVD deaths were identified. A genetic predisposition to ever smoking was significantly associated with CVD mortality; the multivariable-adjusted HR of CVD mortality was 1.07 (95% CI: 1.03–1.12), with a per-SD increment in the wGRS. However, the Mendelian randomization analysis did not support a causal relationship between ever smoking and CVD mortality (OR, 1.13; 95% CI: 0.87–1.45). Additionally, the Dietary Approaches to Stop Hypertension (DASH) score significantly modified the association between the smoking wGRS and CVD mortality; the association between a genetic predisposition to smoking and CVD mortality was only observed among individuals with a low DASH score (P- interaction = 0.004). Conclusions A genetic predisposition to smoking was associated with CVD mortality in the Chinese population. In addition, we detected a significant interaction showing higher CVD mortality related to genetically determined smoking among those with lower DASH scores. [ABSTRACT FROM AUTHOR]

Background: Telomere attrition has been proposed as a hallmark of aging. We previously reported on the association between blood leukocyte telomere length (LTL) at midlife and risk of chronic diseases and mortality.Methods: In this study, we investigated the effect of midlife LTL and genetic proxies on 5 markers of aging outcomes, namely handgrip strength, timed up-and-go (TUG), Singapore-modified Mini-Mental State Examination (SM-MMSE) scores, anxiety, and depression indices, measured after a median 20-year follow-up in the Singapore Chinese Health Study (N = 9581).Results: We observed a significant association between midlife LTL and handgrip strength later in life (p = .004, padjust = .020), as well as a nominal significant association between midlife LTL and TUG later in life (p = .036, padjust = .180). The weighted Genetic Risk Score (wGRS) comprising 15 previously reported LTL reducing loci in East Asians was not significantly associated with handgrip strength. However, results from Structural Equation Modeling showed that the effect of this wGRS on handgrip strength was mediated through LTL (proportion of wGRS effect on handgrip strength mediated through LTL = 33.3%, p = .010).Conclusions: Longer midlife LTL was associated with increased handgrip strength later in life. [ABSTRACT FROM AUTHOR]

Background: Adult height has been associated with handgrip strength, which is a surrogate marker of physical frailty. However, it is uncertain if this association is causative or due to confounding bias., Methods: We evaluated pairwise associations among handgrip strength, adult height, and genetically determined height (using a polygenic score [PGS] for height in a mediation framework and a 2-sample Mendelian randomization approach) by means of a multivariable regression model using a prospective cohort of Chinese living in Singapore. We additionally evaluated pathway enrichments of height-related genes in relation to increased handgrip strength to discover common biological mechanisms underlying associations of genetically determined height with handgrip strength., Results: Height PGS exhibited a positive association with handgrip strength at late life after adjusting for midlife body weight and other baseline exposures (cigarette smoking, education, and physical activity status, p = 1.2 × 10-9). Approximately 66.4% of the total effect of height PGS on handgrip strength was mediated through adult height (βindirect-effect = 0.034, pindirect-effect = 1.4 × 10-40). Two-sample Mendelian randomization evaluations showed a consistent causal relationship between increased height and increased handgrip strength in late life (p between 6.6 × 10-4 and 3.9 × 10-18), with insignificant horizontal pleiotropic effects (pMR-Egger intercept = 0.853). Pathway analyses of genes related to both increased adult height and handgrip strength revealed enrichment in ossification and adipogenesis pathways (padj between .034 and 6.8 × 10-4)., Conclusions: The study highlights a potentially causal effect between increased adult height and increased handgrip strength in late life, which may be explained by related biological processes underlying the preservation of muscle mass and strength in aging., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)