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Understanding how gene-environment interactions (GEIs) influence the circulating proteome could aid in biomarker discovery and validation. The presence of GEIs can be inferred from single nucleotide polymorphisms that associate with phenotypic variability - termed variance quantitative trait loci (vQTLs). Here, vQTL association studies are performed on plasma levels of 1463 proteins in 52,363 UK Biobank participants. A set of 677 independent vQTLs are identified across 568 proteins. They include 67 variants that lack conventional additive main effects on protein levels. Over 1100 GEIs are identified between 101 proteins and 153 environmental exposures. GEI analyses uncover possible mechanisms that explain why 13/67 vQTL-only sites lack corresponding main effects. Additional analyses also highlight how age, sex, epistatic interactions and statistical artefacts may underscore associations between genetic variation and variance heterogeneity. This study establishes the most comprehensive database yet of vQTLs and GEIs for the human proteome., (© 2024. The Author(s).)

Ugi reactions and related variations are proven to be atom and step-economic strategies for construction of highly valuable peptide-like skeletons and nitrogenous heterocycles. The development of structurally diverse range of novel catalytic systems and the discovery of new approaches to accommodate a broader scope of terminating reagents for asymmetric Ugi four-component reaction is still in high demand. Here, we report a strategy that enables enantioselective Ugi four-component and Ugi-azide reactions employing anionic stereogenic-at-cobalt(III) complexes as catalysts. The key nitrilium intermediates, generated through the nucleophilic addition of isocyanides to the chiral ion-pair which consists of stereogenic-at-cobalt(III) complexes counteranion and a protonated iminium, are trapped by either carboxylic acids or in situ-generated hydrazoic acid, delivering α-acylamino amides and α-aminotetrazoles in good to excellent enantioselectivities (up to 99:1 e.r.)., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

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.

Calcium orthophosphates (CaPs) are important in geology, biomineralization, animal metabolism and biomedicine, and constitute a structurally and chemically diverse class of minerals. In the case of dicalcium phosphates, ever since brushite (CaHPO 4 ·2H 2 O, dicalcium phosphate dihydrate, DCPD) and monetite (CaHPO 4 , dicalcium phosphate, DCP) were first described in 19 th century, the form with intermediary chemical formula CaHPO 4 ·H 2 O (dicalcium phosphate monohydrate, DCPM) has remained elusive. Here, we report the synthesis and crystal structure determination of DCPM. This form of CaP is found to crystallize from amorphous calcium hydrogen phosphate (ACHP) in water-poor environments. The crystal structure of DCPM is determined to show a layered structure with a monoclinic symmetry. DCPM is metastable in water, but can be stabilized by organics, and has a higher alkalinity than DCP and DCPD. This study serves as an inspiration for the future exploration of DCPM's potential role in biomineralization, or biomedical applications.

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

In the originally published version of this Article, financial support was not fully acknowledged. The sentence "KS was supported by the 'Biomedical Research Program' funds at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation" has been added to the acknowledgement section in both the PDF and HTML versions of the Article.

Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.