Blood protein assessment of leading incident diseases and mortality in the UK Biobank.

The circulating proteome offers insights into the biological pathways that underlie disease. Here, we test relationships between 1,468 Olink protein levels and the incidence of 23 age-related diseases and mortality in the UK Biobank (n = 47,600). We report 3,209 associations between 963 protein levels and 21 incident outcomes. Next, protein-based scores (ProteinScores) are developed using penalized Cox regression. When applied to test sets, six ProteinScores improve the area under the curve estimates for the 10-year onset of incident outcomes beyond age, sex and a comprehensive set of 24 lifestyle factors, clinically relevant biomarkers and physical measures. Furthermore, the ProteinScore for type 2 diabetes outperforms a polygenic risk score and HbA1c-a clinical marker used to monitor and diagnose type 2 diabetes. The performance of scores using metabolomic and proteomic features is also compared. These data characterize early proteomic contributions to major age-related diseases, demonstrating the value of the plasma proteome for risk stratification.

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals.

INTRODUCTION: Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. METHODS: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. RESULTS: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. DISCUSSION: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. HIGHLIGHTS: Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.

Whey Protein Isolate Composites as Potential Scaffolds for Cultivated Meat.

Modern food technology has given rise to numerous alternative protein sources in response to a growing human population and the negative environmental impacts of current food systems. To aid in achieving global food security, one such form of alternative protein being investigated is cultivated meat, which applies the principles of mechanical and tissue engineering to produce animal proteins and meat products from animal cells. Herein, nonmodified and methacrylated whey protein formed hydrogels with methacrylated alginate as potential tissue engineering scaffolds for cultivated meat. Whey protein is a byproduct of dairy processing and was selected because it is an approved food additive and cytocompatible and has shown efficacy in other biomaterial applications. Whey protein and alginate scaffolds were formed via visible light cross-linking in aqueous solutions under ambient conditions. The characteristics of the precursor solution and the physical-mechanical properties of the scaffolds were quantified; while gelation occurred within the homo- and copolymer hydrogels, the integrity of the network was significantly altered with varying components. Qualitatively, the scaffolds exhibited a three-dimensional (3D) interconnected porous network. Whey protein isolate (WPI)-based scaffolds were noncytotoxic and supported in vitro myoblast adhesion and proliferation. The data presented support the hypothesis that the composition of the hydrogel plays a significant role in the scaffold's performance.

FinnGen provides genetic insights from a well-phenotyped isolated population.

Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10-11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.

Genetic map of regional sulcal morphology in the human brain from UK biobank data.

Genetic associations with macroscopic brain structure can provide insights into brain function and disease. However, specific associations with measures of local brain folding are largely under-explored. Here, we conducted large-scale genome- and exome-wide associations of regional cortical sulcal measures derived from magnetic resonance imaging scans of 40,169 individuals in UK Biobank. We discovered 388 regional brain folding associations across 77 genetic loci, with genes in associated loci enriched for expression in the cerebral cortex, neuronal development processes, and differential regulation during early brain development. We integrated brain eQTLs to refine genes for various loci, implicated several genes involved in neurodevelopmental disorders, and highlighted global genetic correlations with neuropsychiatric phenotypes. We provide an interactive 3D visualisation of our summary associations, emphasising added resolution of regional analyses. Our results offer new insights into the genetic architecture of brain folding and provide a resource for future studies of sulcal morphology in health and disease.

DYRK1A antagonists rescue degeneration and behavioural deficits of in vivo models based on amyloid-ß, Tau and DYRK1A neurotoxicity.

Alzheimer's disease (AD) involves pathological processing of amyloid precursor protein (APP) into amyloid-ß and microtubule associated protein Tau (MAPT) into hyperphosphorylated Tau tangles leading to neurodegeneration. Only 5% of AD cases are familial making it difficult to predict who will develop the disease thereby hindering our ability to treat the causes of the disease. A large population who almost certainly will, are those with Down syndrome (DS), who have a 90% lifetime incidence of AD. DS is caused by trisomy of chromosome 21 resulting in three copies of APP and other AD-associated genes, like dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) overexpression. This implies that DYRK1a inhibitors may have therapeutic potential for DS and AD, however It is not clear how overexpression of each of these genes contributes to the pathology of each disease as well as how effective a DYRK1A inhibitor would be at suppressing any of these. To address this knowledge gap, we used Drosophila models with human Tau, human amyloid-ß or fly DYRK1A (minibrain (mnb)) neuronal overexpression resulting in photoreceptor neuron degeneration, premature death, decreased locomotion, sleep and memory loss. DYRK1A small molecule Type 1 kinase inhibitors (DYR219 and DYR533) were effective at suppressing these disease relevant phenotypes confirming their therapeutic potential.

The Open-Access European Prevention of Alzheimer's Dementia (EPAD) MRI dataset and processing workflow.

The European Prevention of Alzheimer Dementia (EPAD) is a multi-center study that aims to characterize the preclinical and prodromal stages of Alzheimer's Disease. The EPAD imaging dataset includes core (3D T1w, 3D FLAIR) and advanced (ASL, diffusion MRI, and resting-state fMRI) MRI sequences. Here, we give an overview of the semi-automatic multimodal and multisite pipeline that we developed to curate, preprocess, quality control (QC), and compute image-derived phenotypes (IDPs) from the EPAD MRI dataset. This pipeline harmonizes DICOM data structure across sites and performs standardized MRI preprocessing steps. A semi-automated MRI QC procedure was implemented to visualize and flag MRI images next to site-specific distributions of QC features - i.e. metrics that represent image quality. The value of each of these QC features was evaluated through comparison with visual assessment and step-wise parameter selection based on logistic regression. IDPs were computed from 5 different MRI modalities and their sanity and potential clinical relevance were ascertained by assessing their relationship with biological markers of aging and dementia. The EPAD v1500.0 data release encompassed core structural scans from 1356 participants 842 fMRI, 831 dMRI, and 858 ASL scans. From 1356 3D T1w images, we identified 17 images with poor quality and 61 with moderate quality. Five QC features - Signal to Noise Ratio (SNR), Contrast to Noise Ratio (CNR), Coefficient of Joint Variation (CJV), Foreground-Background energy Ratio (FBER), and Image Quality Rate (IQR) - were selected as the most informative on image quality by comparison with visual assessment. The multimodal IDPs showed greater impairment in associations with age and dementia biomarkers, demonstrating the potential of the dataset for future clinical analyses.

Genetic associations of protein-coding variants in human disease.

Genome-wide association studies (GWAS) have identified thousands of genetic variants linked to the risk of human disease. However, GWAS have so far remained largely underpowered in relation to identifying associations in the rare and low-frequency allelic spectrum and have lacked the resolution to trace causal mechanisms to underlying genes1. Here we combined whole-exome sequencing in 392,814 UK Biobank participants with imputed genotypes from 260,405 FinnGen participants (653,219 total individuals) to conduct association meta-analyses for 744 disease endpoints across the protein-coding allelic frequency spectrum, bridging the gap between common and rare variant studies. We identified 975 associations, with more than one-third being previously unreported. We demonstrate population-level relevance for mutations previously ascribed to causing single-gene disorders, map GWAS associations to likely causal genes, explain disease mechanisms, and systematically relate disease associations to levels of 117 biomarkers and clinical-stage drug targets. Combining sequencing and genotyping in two population biobanks enabled us to benefit from increased power to detect and explain disease associations, validate findings through replication and propose medical actionability for rare genetic variants. Our study provides a compendium of protein-coding variant associations for future insights into disease biology and drug discovery.

Oxidations of pyrrolidines and piperidines to afford CH-functionalized isopropyl-1-carboxylate congeners.

This article describes the action of iodine(III) reagents [diacetoxyiodobenzene, PhI(OAc)2, and iodosobenzene, (PhIO)n] in conjunction with TMSBr which act as functional bromine equivalents in unique oxidations of saturated, carbamate protected N-heterocycles. Interestingly, during this work, treatment of the same carbamates with molecular bromine alone afforded similar products, which were sequestered by the solvent methanol.

Sequential Knoevenagel [4+1] Cycloaddition-Condensation-Aza-Friedel-Crafts Intramolecular Cyclization: A 4-Center-3-Component Reaction Toward Tunable Fluorescent Indolizine Tetracycles.

A two-step multicomponent reaction oxidation protocol is reported herein, which affords novel tunable fluorescent tetracyclic indolizines. The procedure involves a novel 4-center-3-component reaction, which proceeds via a sequential Knoevenagel condensation, [4+1] cycloaddition, and imine condensation to afford imino-indolizines. Products then undergo cyclization and are oxidized in situ to afford fluorescent tetracycles, which are readily tunable through modification of diversity elements.

Inhibition of GATA2 in prostate cancer by a clinically available small molecule.

Castration-resistant prostate cancer (CRPC) remains highly lethal and in need of novel, actionable therapeutic targets. The pioneer factor GATA2 is a significant prostate cancer (PC) driver and is linked to poor prognosis. GATA2 directly promotes androgen receptor (AR) gene expression (both full-length and splice-variant) and facilitates AR binding to chromatin, recruitment of coregulators, and target gene transcription. Unfortunately, there is no clinically applicable GATA2 inhibitor available at the moment. Using a bioinformatics algorithm, we screened in silico 2650 clinically relevant drugs for a potential GATA2 inhibitor. Validation studies used cytotoxicity and proliferation assays, global gene expression analysis, RT-qPCR, reporter assay, reverse phase protein array analysis (RPPA), and immunoblotting. We examined target engagement via cellular thermal shift assay (CETSA), ChIP-qPCR, and GATA2 DNA-binding assay. We identified the vasodilator dilazep as a potential GATA2 inhibitor and confirmed on-target activity via CETSA. Dilazep exerted anticancer activity across a broad panel of GATA2-dependent PC cell lines in vitro and in a PDX model in vivo. Dilazep inhibited GATA2 recruitment to chromatin and suppressed the cell-cycle program, transcriptional programs driven by GATA2, AR, and c-MYC, and the expression of several oncogenic drivers, including AR, c-MYC, FOXM1, CENPF, EZH2, UBE2C, and RRM2, as well as of several mediators of metastasis, DNA damage repair, and stemness. In conclusion, we provide, via an extensive compendium of methodologies, proof-of-principle that a small molecule can inhibit GATA2 function and suppress its downstream AR, c-MYC, and other PC-driving effectors. We propose GATA2 as a therapeutic target in CRPC.

Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the GIPR Region.

There is considerable interest in GIPR agonism to enhance the insulinotropic and extrapancreatic effects of GIP, thereby improving glycemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the GIPR locus. Using Bayesian multitrait colocalization, we identified a GIPR missense variant, rs1800437 (G allele; E354), as the putatively causal variant shared among fasting GIP levels, glycemic traits, and adiposity-related traits (posterior probability for colocalization [PPcoloc] > 0.97; PP explained by the candidate variant [PPexplained] = 1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in APOE (rs7412; distance to E354 ∼770 Kb; R 2 with E354 = 0.004; PPcoloc > 0.99; PPexplained = 1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (odds ratio [OR] per copy of E354 after adjustment 1.03; 95% CI 1.02, 1.04; P = 0.003). Instead, E354's association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272 (R 2 with E354 = 0.27), an intronic variant in SNRPD2 (OR for E354 after adjustment for rs1964272: 1.01; 95% CI 0.99, 1.03; P = 0.06). We demonstrate that associations with GIP and anthropometric and glycemic traits are driven by genetic signals distinct from those driving CAD and lipid traits in the GIPR region and that higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect that has yet to be assessed in clinical trials.

A fast and efficient colocalization algorithm for identifying shared genetic risk factors across multiple traits.

Genome-wide association studies (GWAS) have identified thousands of genomic regions affecting complex diseases. The next challenge is to elucidate the causal genes and mechanisms involved. One approach is to use statistical colocalization to assess shared genetic aetiology across multiple related traits (e.g. molecular traits, metabolic pathways and complex diseases) to identify causal pathways, prioritize causal variants and evaluate pleiotropy. We propose HyPrColoc (Hypothesis Prioritisation for multi-trait Colocalization), an efficient deterministic Bayesian algorithm using GWAS summary statistics that can detect colocalization across vast numbers of traits simultaneously (e.g. 100 traits can be jointly analysed in around 1 s). We perform a genome-wide multi-trait colocalization analysis of coronary heart disease (CHD) and fourteen related traits, identifying 43 regions in which CHD colocalized with ≥1 trait, including 5 previously unknown CHD loci. Across the 43 loci, we further integrate gene and protein expression quantitative trait loci to identify candidate causal genes.

Suzuki Coupling of Protected Aryl Diazonium Ions: Expanding the Knowledge of Triazabutadiene Compatible Reactions.

Aryl diazonium ions are important in synthesis and chemical biology, and the acid-labile triazabutadiene can protect this handle for future use. We report a Suzuki coupling strategy that is compatible with the triazabutadiene scaffold, expanding the scope of synthetically available triazabutadienes. Shown herein, the triazabutadiene scaffold remains intact and reactive after coupling, as demonstrated by releasing the aryl diazonium ion to label a tyrosine-rich model protein.

MR-Clust: clustering of genetic variants in Mendelian randomization with similar causal estimates.

MOTIVATION: Mendelian randomization is an epidemiological technique that uses genetic variants as instrumental variables to estimate the causal effect of a risk factor on an outcome. We consider a scenario in which causal estimates based on each variant in turn differ more strongly than expected by chance alone, but the variants can be divided into distinct clusters, such that all variants in the cluster have similar causal estimates. This scenario is likely to occur when there are several distinct causal mechanisms by which a risk factor influences an outcome with different magnitudes of causal effect. We have developed an algorithm MR-Clust that finds such clusters of variants, and so can identify variants that reflect distinct causal mechanisms. Two features of our clustering algorithm are that it accounts for differential uncertainty in the causal estimates, and it includes 'null' and 'junk' clusters, to provide protection against the detection of spurious clusters. RESULTS: Our algorithm correctly detected the number of clusters in a simulation analysis, outperforming methods that either do not account for uncertainty or do not include null and junk clusters. In an applied example considering the effect of blood pressure on coronary artery disease risk, the method detected four clusters of genetic variants. A post hoc hypothesis-generating search suggested that variants in the cluster with a negative effect of blood pressure on coronary artery disease risk were more strongly related to trunk fat percentage and other adiposity measures than variants not in this cluster. AVAILABILITY AND IMPLEMENTATION: MR-Clust can be downloaded from https://github.com/cnfoley/mrclust. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

5-Endo Trig Oxidative Radical Cyclizations of Ugi-3CR Products toward 1,4-Imidazolidinones.

A 5-endo trig oxidative radical cyclization of benzylamine-derived Ugi three-component reaction products rapidly affords imidazolidinones with three diversity elements. This adaptation of our previously described multicomponent reaction-oxidation methodology further showcases manipulation of the diversity elements in multicomponent reaction products via oxidative radical cyclizations, which generates highly decorated privileged heterocycles.

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.