Meta-analysis of 49(cid:0)549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels
This study illustrates that GWAS with high-scale imputation may still help to unravel the biological mechanism behind circulating lipid levels and identifies more new rare and low-frequency functional variants associated with circulating lipid levels.
New SNPs linked to inflammatory biomarkers in a highly admixed Brazilian population are identified, including a missense variant in an olfactory receptor gene linked to MCP-1, which may be biologically important for inflammation and could affect the risk of cardiometabolic diseases.
J. Leite, G. F. L. Pascoal, G. B. S. Duarte et al.· Frontiers in Immunology· 0 citations
BACKGROUND
Type 1 diabetes (T1D) is a common disease. Although genome-wide association studies (GWASs) have identified hundreds of associated single nucleotide polymorphisms (SNPs), very few T1D GWAS have simultaneously addressed both Asian and European populations.
METHODS
Here, we conducted a large-scale trans-ancestry meta-analysis including 680,539 European individuals (12,525 T1D cases and 668,014 controls) and 133,251 Asian individuals (1,219 T1D cases and 132,032 controls) to identify genetic associations with T1D. Subsequently, fine-mapping and Summary-data-based Mendelian randomization (SMR) analyses were performed to further refine T1D-related genetic signals.
RESULTS
We identified 27 T1D-associated loci, including 8 potentially novel loci (near CDKAL1, NRSN1, FAM65B, LRRC16A, TULP1, SLC17A3, LRIG2, C6orf1). Fine-mapping was performed and helped pinpoint 7 putative causal variants (posterior probability, PP > 0.95) with T1D. Among them, rs9366622 (PP = 0.976) and rs1165190 (PP = 0.996) are located near LRRC16A and SLC17A3, respectively. These two variants are the lead SNPs of identified novel loci. SMR analysis identified a putative risk gene (U91328.19) at the novel locus SLC17A3-rs1165190, whose expression level is causally associated with T1D.
CONCLUSIONS
These findings suggest that, for T1D, increasing ancestral diversity in genetic studies helps identify core genes and provides new insights into pathogenesis.
BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder resulting from a complex interplay of multiple factors. Recent hypotheses suggest a potential role of selenium and selenoproteins in AD pathogenesis. However, the causality relationship between them remains to be elucidated.ObjectiveThis study investigates the causal link between selenoproteins and AD risk.MethodsWe analyzed the data by leveraging genome-wide association studies from European cohorts (90,338 AD patients and 1,036,225 controls) and expression quantitative trait loci (eQTLs) from eQTLGen (31,684 individuals) and GTEx v8 (838 individuals). Mendelian randomization and summary data-based Mendelian randomization were applied to assess the potential causal associations between selenoproteins and AD. To further confirm these genetic associations at the clinical level, we conducted a case-control study to evaluate the levels of four differentially expressed selenoproteins in peripheral blood in individuals with AD and cognitively normal controls.ResultsOur analysis revealed that four selenoproteins, including selenoprotein S (SEPH2) and selenoprotein M (SELENOM), glutathione peroxidase 4 (GPX4) and thioredoxin reductase 2 (TXNRD2), were correlated with a decreased risk of AD. The levels of GPX4, SELENOM, and TXNRD2 were found to be significantly downregulated in AD patients compared to controls in the case-control validation study, supporting the change identified in our genetic analysis.ConclusionsThis study provides genetic and clinical evidence that specific selenoproteins are associated with a decreased risk of AD. The findings highlight the potential role of these proteins in AD pathophysiology and suggest their promise as biomarkers or therapeutic targets, warranting further investigation.
Peixin Jiang, Sibo Peng, Yanling Huang et al.· Journal of Alzheimer's Disea...· 0 citations
Bladder cancer is the ninth most common cancer worldwide, caused by genetic and environmental risk factors. Here, we report the findings of a multi-population meta-analysis of genome-wide association studies, including 32,470 individuals with and 1,753,462 without bladder cancer. We identify 70 independent risk loci, of which 43 are novel. Using a 70-marker polygenic risk score (HR = 1.63 per standard deviation), we increase the area under the curve from 0.71 (baseline risk model) to 0.75. Integrative analyses reveal the enrichment of the associated variants within accessible chromatin regions, and of the prioritized genes within pathways for xenobiotic metabolism and smoking behavior. Specifically, we show that the 15q25.1 variant rs71581744-ACCCC/A co-localizes with tissue-specific CHRNA3 expression, modulates mRNA stability, and associates with risk of muscle-invasive bladder cancer among current smokers. Together, these findings substantially expand the known genetic architecture of bladder cancer risk and highlight the germline regulation of smoking behavior as a mechanism driving bladder cancer susceptibility. This study integrates genetic data from diverse populations to identify 70 loci linked to bladder cancer risk, including 43 novel, and uses experimental approaches to uncover how inherited variation influences this risk in the context of smoking.
L. Prokunina-Olsson, O. Flórez-Vargas, Michael G. Levin et al.· Nature Communications· 0 citations
Epidemiological and Mendelian randomization studies have reported an inverse relationship between lipoprotein(a) [Lp(a)] concentration and type 2 diabetes (T2D), although findings have not been uniform across studies. We hypothesized that genetic variation at the
LPA
locus may contribute to T2D development beyond circulating Lp(a) concentration alone, and therefore aimed to investigate the association between common
LPA
variation and incident T2D.
We analysed 5058 male participants from the Aragon Workers’ Health Study with approximately 15 years of follow-up. T2D was defined as the presence of antidiabetic treatment or HbA1c ≥ 6.5%. Common
LPA
single-nucleotide variants (SNVs) with a minor allele frequency ≥ 1% were selected. Several weighted
LPA
genetic scores were constructed, with the 15-SNV score defined as the primary
LPA
genetic score and alternative and more restricted scores evaluated in sensitivity analyses. Associations of single
LPA
variants and
LPA
genetic scores with incident T2D were assessed using multivariable logistic regression models adjusted for age, body mass index, ln-transformed Lp(a), and a T2D polygenic risk score. False discovery rate correction was applied to account for multiple testing. Robustness was assessed using leave-one-out analyses and Cox proportional hazards models.
Among 4744 participants free of T2D at baseline, 578 (12.2%) developed incident T2D. Baseline Lp(a) concentrations were lower in participants who developed incident T2D than in those who remained free of T2D (12.6 [5.0–32.5] versus 17.0 [6.1–40.0] mg/dL;
p
< 0.001). No individual
LPA
SNV remained significantly associated with incident T2D. In contrast, the primary 15-SNV
LPA
genetic score was associated with incident T2D after adjustment for measured baseline Lp(a) concentration (odds ratio per one-standard-deviation increase 1.17, 95% confidence interval 1.07–1.29;
p
= 0.001). The 13-SNV, 12-SNV, 10-coding/splice, and 2-SNV raising-Lp(a) scores were also significantly associated with incident T2D after false discovery rate correction. The association with the 15-SNV
LPA
genetic score was supported by leave-one-out and Cox analyses.
A 15-SNV
LPA
genetic score was associated with incident T2D after adjustment for measured baseline Lp(a) concentration and a T2D polygenic risk score. These findings suggest that common
LPA
variation represented by the 15-SNV genetic score may contribute to T2D risk through mechanisms not fully captured by circulating Lp(a) concentration alone.
P. Corredoira, Daniel Bello Álvarez, Itziar Lamiquiz Moneo et al.· Cardiovascular Diabetology· 0 citations
Background Genome-wide aggregated trans-effects (GATE) analysis is a novel method in which trans-effects on gene expression (as transcript or protein) are combined with SNP-trait association data to identify core genes that directly influence the trait. The objective of this study was to identify core genes for blood pressure. Methods We undertook GWASs of mean arterial pressure (MAP) and and body mass index (BMI) in 373,882 individuals aged less than 60 in the Our Future Health (OFH) cohort. Using summary statistics from GWASs of circulating proteins on the SomaScan and Olink platforms, we tested for association of GATE scores (predicted levels of each protein based on trans-effects) with MAP. We confirmed replication of top associations in an independent cohort. Results The strongest GATE score association with MAP was for LPL (lipoprotein lipase). Higher genetically predicted circulating levels of LPL were associated with lower MAP but higher BMI. GATE scores for three other proteins involved in lipid handling – CD300LG, ADIPOQ, TIMP4 – were also associated with lower MAP but higher BMI. GATE scores for all four of these proteins were inversely associated with chylomicron triglyceride (measured as XXL-VLDL-TG by NMR spectroscopy). The associations of GATE scores for ANGPTL3 and ANGPTL4, which regulate LPL, were consistent with a causal role of LPL in lowering XXL-VLDL-TG and MAP. Conclusions These results point to a key role in hypertension for proteins that regulate post-prandial clearance of triglyceride-rich lipoproteins, independently of adiposity.
S. Braichenko, A. Iakovliev, Jay Dyer et al.· bioRxiv· 0 citations
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