Biology subjects

Qiu, C.

Publications and source records attributed to Qiu, C..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2

Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G-protein-coupled receptors with key roles in regulating lipolysis and free fatty acid formation in humans. It is deeply involved in many pathophysiological processes and serves as an attractive target for the treatment of neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases. Here, we report four cryo-EM structures of human HCAR2-Gi1 complexes with or without agonists, including the drugs niacin and acipimox, and the highly subtype-specific agonist MK-6892. Combined with molecular docking and functional analysis, we have revealed the recognition mechanism of HCAR2 for different agonists and summarized the general pharmacophore features of HCAR2 agonists, which are based on three key residues R1113.36, S17945.52, and Y2847.43. Notably, the MK-6892-HCAR2 structure shows an extended binding pocket relative to other agonist-bound HCAR2 complexes. In addition, the key residues that determine the ligand selectivity between the HCAR2 and HCAR3 are also illuminated. Our findings provide structural insights into the ligand recognition, selectivity, activation, and G protein coupling mechanism of HCAR2, which sheds light on the design of new HCAR2-targeting drugs for greater efficacy, higher selectivity, and fewer or no side effects.

cell biology↗

bioRxiv2023

Multi-omics of the gut microbial ecosystem in the immunotherapy resistance in microsatellite instability-high gastrointestinal cancer patients

Despite the encouraging efficacy of anti-PD-1/PD-L1 immunotherapy in microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) advanced gastrointestinal cancer, many patients exhibit primary or acquired resistance. Using multi-omics approaches, we interrogated gut microbiome, blood metabolome and cytokines/chemokines of MSI-H/dMMR advanced gastrointestinal cancer patients (N=77) and identified a number of microbes (e.g. Alistipes putredinis) and metabolites (e.g. arginine and SCFA) highly associated with primary resistance. Fecal microbiota transplantation of patients stool replicated the clinical responsiveness as well as certain molecular signatures. Based on the clinical microbiome data, we developed a predictive machine learning model for primary resistance and achieved accuracy at 0.83 on an external validation set. Furthermore, several microbes were pinpointed which gradually changed during the process of acquired resistance. In summary, our study demonstrated the essential role of gut microbiome in drug resistance, and this could be utilized as a preventative diagnosis tool as well as therapeutic targets in the future.

cancer biology↗

bioRxiv2023

Widespread epistasis shapes RNA Polymerase II active site function and evolution

Multi-subunit RNA Polymerases (msRNAPs) are responsible for transcription in all kingdoms of life. These enzymes rely on dynamic, highly conserved active site domains such as the so-called "trigger loop" (TL) to accomplish steps in the transcription cycle. Mutations in the RNA polymerase II (Pol II) TL confer a spectrum of biochemical and genetic phenotypes that suggest two main classes, which decrease or increase catalysis or other nucleotide addition cycle (NAC) events. The Pol II active site relies on networks of residue interactions to function, and mutations likely perturb these networks in ways that may alter mechanisms. We have undertaken a structural genetics approach to reveal residue interactions within and surrounding the Pol II TL - determining its "interaction landscape" - by deep mutational scanning in Saccharomyces cerevisiae Pol II. This analysis reveals connections between TL residues and surrounding domains, demonstrating that TL function is tightly coupled to its specific enzyme context.

genetics↗

bioRxiv2022

Characterization of RNA Polymerase II Trigger Loop Mutations using Molecular Dynamics Simulations and Machine Learning

Catalysis and fidelity of multisubunit RNA polymerases rely on a highly conserved active site domain called the trigger loop (TL), which achieves roles in transcription through conformational changes and interaction with NTP substrates. The mutations of TL residues cause distinct effects on catalysis including hypo- and hyperactivity and altered fidelity. We applied molecular dynamics simulation (MD) and machine learning (ML) techniques to characterize TL mutations in the Saccharomyces cerevisiae RNA Polymerase II (Pol II) system. We did so to determine relationships between individual mutations and phenotypes and to associate phenotypes with MD simulated structural alterations. Using fitness values of mutants under various stress conditions, we modeled phenotypes along a spectrum of continual values. We found that ML could predict the phenotypes with 0.68 R2 correlation from amino acid sequences alone. It was more difficult to incorporate MD data to improve predictions from machine learning, presumably because MD data is too noisy and possibly incomplete to directly infer functional phenotypes. However, a variational auto-encoder model based on the MD data allowed the clustering of mutants with different phenotypes based on structural details. Overall, we found that lethal mutations tended to increase distances of TL residues to the NTP substrate, while viable loss-of-function (LOF) substitutions tended to confer an increase in distances between TL and bridge helix (BH). In contrast, GOF mutants generally have a disrupting effect on hydrophobic contacts among TL and nearby helices. AUTHOR SUMMARYRNA polymerase II (Pol II) synthesizes RNA with the help of an active site domain called trigger loop (TL). The mutations of TL cause changes in the activity of Pol II that could range from gain-of function (GOF) to loss-of-function (LOF) or lethal. This study provides a systematic characterization of the structural and functional outcomes of the TL mutations using molecular dynamics (MD) simulations and machine learning (ML). We obtained functional phenotypes of mutants by ML using the genetic fitness scores as the input. We revealed that mutant TL sequences could predict the functional outcomes at a relatively high correlation. Then, we performed MD simulations to relate the structural information to the phenotypes. The analysis of the MD data suggested that the lethal mutants had increased distances between the TL and the substrate, while a subset of LOF mutants showed increased distances between TL and another active site domain called bridge helix (BH). On the other hand, GOF mutants had effects on the hydrophobic interactions around the active site. Overall, this study enhances our understanding of the effects of TL mutations to the Pol II function.

biophysics↗

bioRxiv2022

Single cell, whole embryo phenotyping of pleiotropic disorders of mammalian development

Mouse models are a critical tool for studying human diseases, particularly developmental disorders, as well as for advancing our general understanding of mammalian biology. However, it has long been suspected that conventional approaches for phenotyping are insufficiently sensitive to detect subtle defects throughout the developing mouse. Here we set out to establish single cell RNA sequencing (sc-RNA-seq) of the whole embryo as a scalable platform for the systematic molecular and cellular phenotyping of mouse genetic models. We applied combinatorial indexing-based sc-RNA-seq to profile 101 embryos of 26 genotypes at embryonic stage E13.5, altogether profiling gene expression in over 1.6M nuclei. The 26 genotypes include 22 mouse mutants representing a range of anticipated severities, from established multisystem disorders to deletions of individual enhancers, as well as the 4 wildtype backgrounds on which these mutants reside. We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibited changes in dozens of trajectories (e.g., the pleiotropic consequences of altering the Sox9 regulatory landscape) whereas others showed phenotypes affecting specific subsets of cells. We also identify differences between widely used wildtype strains, compare phenotyping of gain vs. loss of function mutants, and characterise deletions of topological associating domain (TAD) boundaries. Intriguingly, even among these 22 mutants, some changes are shared by heretofore unrelated models, suggesting that developmental pleiotropy might be "decomposable" through further scaling of this approach. Overall, our findings show how single cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution.

genomics↗

bioRxiv2022

Efficient neural codes naturally emerge through gradient descent learning

Animal sensory systems are more sensitive to common features in the environment than uncommon features. For example, small deviations from the more frequently encountered horizontal orientations can be more easily detected than small deviations from the less frequent diagonal ones. Here we find that artificial neural networks trained to recognize objects also have patterns of sensitivity that match the statistics of features in images. To interpret these findings, we show mathematically that learning with gradient descent in deep neural networks preferentially creates representations that are more sensitive to common features, a hallmark of efficient coding. This result suggests that efficient coding naturally emerges from gradient-like learning on natural stimuli.

neuroscience↗

bioRxiv2022

Characterization of Hydrophobic Interactions of SARS-CoV-2 and MERS-CoV Spike Protein Fusion Peptides Using Single Molecule Force Measurements

We address the challenge of understanding how hydrophobic interactions are encoded by fusion peptide sequences within coronavirus (CoV) spike proteins. Within the fusion peptides of SARS-CoV-2 and MERS-CoV, a largely conserved peptide sequence called FP1 (SFIEDLLFNK and SAIEDLLFDK in SARS-2 and MERS, respectively) has been proposed to play a key role in encoding hydrophobic interactions that drive viral-host cell membrane fusion. While a non-polar triad (LLF) is common to both FP1 sequences, and thought to dominate the encoding of hydrophobic interactions, FP1 from SARS and MERS differ in two residues (Phe 2 versus Ala 2 and Asn 9 versus Asp 9, respectively). Here we explore if single molecule force measurements can quantify hydrophobic interactions encoded by FP1 sequences, and then ask if sequence variations between FP1 from SARS and MERS lead to significant differences in hydrophobic interactions. We find that both SARS-2 and MERS wild-type FP1 generate measurable hydrophobic interactions at the single molecule level, but that SARS-2 FP1 encodes a substantially stronger hydrophobic interaction than its MERS counterpart (1.91 {+/-} 0.03 nN versus 0.68 {+/-} 0.03 nN, respectively). By performing force measurements with FP1 sequences with single amino acid substitutions, we determine that a single residue mutation (Phe 2 versus Ala 2) causes the almost threefold difference in the hydrophobic interaction strength generated by the FP1 of SARS-2 versus MERS, despite the presence of LLF in both sequences. Infrared spectroscopy and circular dichroism measurements support the proposal that the outsized influence of Phe 2 versus Ala 2 on the hydrophobic interaction arises from variation in the secondary structure adopted by FP1. Overall, these insights reveal how single residue diversity in viral fusion peptides, including FP1 of SARS-CoV-2 and MERS-CoV, can lead to substantial changes in intermolecular interactions proposed to play a key role in viral fusion, and hint at strategies for regulating hydrophobic interactions of peptides in a range of contexts. SIGNIFICANCEFusion of coronaviruses (CoVs) and host cells is mediated by the insertion of the fusion peptide (FP) of the viral spike protein into the host cell membrane. Hydrophobic interactions between FPs with their host cell membranes regulate the viral membrane fusion process and are key to determining infection ability. However, it is not fully understood how the amino acid sequences in FPs mediate hydrophobic interactions. We use single-molecule force measurements to characterize hydrophobic interactions of FPs from SARS-CoV-2 and MERS-CoV. Our findings provide insight into the mechanisms by which the amino acid composition of FPs encodes hydrophobic interactions and their implications for fusion activity critical to the spread of infection.

biophysics↗

bioRxiv2022

Omicron booster in ancestral strain vaccinated mouse augments protective immunities against both the Delta and Omicron variants

A booster vaccination is called for constraining the evolving epidemic of SARS-CoV-2. However, the necessity of a new COVID-19 vaccine is currently unclear. To compare the effect of an Omicron-matched S DNA vaccine and an ancestral S DNA vaccine in boosting cross-reactive immunities, we firstly immunized mice with two-dose of a DNA vaccine encoding the spike protein of the ancestral Wuhan strain. Then the mice were boosted with DNA vaccines encoding spike proteins of either the Wuhan strain or the Omicron variant. Specific antibody and T cell responses were measured at 4 weeks post boost. Our data showed that the Omicron-matched vaccine efficiently boosted RBD binding antibody and neutralizing antibody responses against both the Delta and the Omicron variants. Of note, antibody responses against the Omicron variant elicited by the Omicron-matched vaccine were much stronger than those induced by the ancestral S DNA vaccine. Meanwhile, CD8+ T cell responses against both the ancestral Wuhan strain and the Omicron strain also tended to be higher in mice boosted by the Omicron-matched vaccine than those in mice boosted with the ancestral S DNA vaccine, albeit no significant difference was observed. Our findings suggest that an Omicron-matched vaccine is preferred for boosting cross-reactive immunities.

immunology↗

bioRxiv2022

Nucleation of the destruction complex on the centrosome accelerates degradation of β-catenin and regulates Wnt signal transmission

Wnt signal transduction is mediated by a protein assembly called the Destruction Complex (DC) made from scaffold proteins and kinases that are essential for transducing extracellular Wnt ligand concentrations to changes in nuclear {beta}-catenin, the pathways transcriptional effector. Recently, DC scaffold proteins have been shown to undergo liquid-liquid phase separation in vivo and in vitro providing evidence for a mesoscale organization of the DC. However, the mesoscale organization of DC at endogenous expression levels and how that organization could play a role in {beta}-catenin processing is unknown. Here we find that the native mesoscale structure is a dynamic biomolecular condensate nucleated by the centrosome. Through a combination of advanced microscopy, CRISPR-engineered custom fluorescent tags, finite element simulations, and optogenetic tools, that allow for independent manipulation of the biophysical parameters that drive condensate formation, we find that a function of DC nucleation by the centrosome is to drive efficient processing of {beta}-catenin by co-localizing DC components to a single reaction hub. We demonstrate that simply increasing the concentration of a single DC kinase onto the centrosome controls {beta}-catenin processing. This simple change in localization completely alters the fate of the Wnt-driven human embryonic stem cell differentiation to mesoderm. Our findings demonstrate the role of nucleators in dynamically controlling the activities of biomolecular condensates and suggest a tight integration between cell cycle progression and Wnt signal transduction.

cell biology↗

bioRxiv2021

Genomics analysis of hexanoic acid exposure in Drosophila species

Drosophila sechellia is a dietary specialist endemic to the Seychelles islands that has evolved to consume the fruit of Morinda citrifolia. When ripe, the fruit of M. citrifolia contains octanoic acid and hexanoic acid, two medium chain fatty acid volatiles that deter and are toxic to generalist insects. D. sechellia has evolved resistance to these volatiles allowing it to feed almost exclusively on this host plant. The genetic basis of octanoic acid resistance has been the focus of multiple recent studies, but the mechanisms that govern hexanoic acid resistance in D. sechellia remain unknown. To understand how D. sechellia has evolved to specialize on M. citrifolia fruit and avoid the toxic effects of hexanoic acid, we exposed adult D. sechellia, D. melanogaster and D. simulans to hexanoic acid and performed RNA sequencing comparing their transcriptional responses to identify D. sechellia specific responses. Our analysis identified many more genes responding transcriptionally to hexanoic acid in the susceptible generalist species than in the specialist D. sechellia. Interrogation of the sets of differentially expressed genes showed that generalists regulated the expression of many genes involved in metabolism and detoxification whereas the specialist primarily downregulated genes involved in the innate immunity. Using these data we have identified interesting candidate genes that may be critically important in aspects of adaptation to their food source that contains high concentrations of HA. Understanding how gene expression evolves during dietary specialization is crucial for our understanding of how ecological communities are built and how evolution shapes trophic interactions.

genomics↗

bioRxiv2021

Systematic reconstruction of the cellular trajectories of mammalian embryogenesis

Mammalian embryogenesis is characterized by rapid cellular proliferation and diversification. Within a few weeks, a single cell zygote gives rise to millions of cells expressing a panoply of molecular programs, including much of the diversity that will subsequently be present in adult tissues. Although intensively studied, a comprehensive delineation of the major cellular trajectories that comprise mammalian development in vivo remains elusive. Here we set out to integrate several single cell RNA-seq datasets (scRNA-seq) that collectively span mouse gastrulation and organogenesis. We define cell states at each of 19 successive stages spanning E3.5 to E13.5, heuristically connect them with their pseudo-ancestors and pseudo-descendants, and for a subset of stages, deconvolve their approximate spatial distributions. Despite being constructed through automated procedures, the resulting trajectories of mammalian embryogenesis (TOME) are largely consistent with our contemporary understanding of mammalian development. We leverage TOME to nominate transcription factors (TF) and TF motifs as key regulators of each branch point at which a new cell type emerges. Finally, to facilitate comparisons across vertebrates, we apply the same procedures to single cell datasets of zebrafish and frog embryogenesis, and nominate "cell type homologs" based on shared regulators and transcriptional states.

developmental biology↗

bioRxiv2021

Thiolutin is a direct inhibitor of RNA Polymerase II

Thiolutin is a natural product transcription inhibitor with an unresolved mode of action. Thiolutin and the related dithiolopyrrolone holomycin chelate Zn2+ and previous studies have concluded that RNA Polymerase II (Pol II) inhibition in vivo is indirect. Here, we present chemicogenetic and biochemical approaches to investigate thiolutins mode of action in Saccharomyces cerevisiae. We identify mutants that alter sensitivity to thiolutin. We provide genetic evidence that thiolutin causes oxidation of thioredoxins in vivo and that thiolutin both induces oxidative stress and interacts functionally with multiple metals including Mn2+ and Cu2+, and not just Zn2+. Finally, we show direct inhibition of RNA polymerase II (Pol II) transcription initiation by thiolutin in vitro in support of classical studies that thiolutin can directly inhibit transcription in vitro. Inhibition requires both Mn2+ and appropriate reduction of thiolutin as excess DTT abrogates its effects. Pause prone, defective elongation can be observed in vitro if inhibition is bypassed. Thiolutin effects on Pol II occupancy in vivo are widespread but major effects are consistent with prior observations for Tor pathway inhibition and stress induction, suggesting that thiolutin use in vivo should be restricted to studies on its modes of action and not as an experimental tool.

molecular biology↗

bioRxiv2021

CD8+ T cell epitope variations suggest a potential antigen presentation deficiency for spike protein of SARS-CoV-2

COVID-19 is caused by a newly identified coronavirus, SARS-CoV-2, and has become a pandemic around the world. The illustration of the immune responses against SARS-CoV-2 is urgently needed for understanding the pathogenesis of the disease and its vaccine development. CD8+ T cells are critical for virus clearance and induce long lasting protection in the host. Here we identified specific HLA-A2 restricted T cell epitopes in the spike protein of SARS-CoV-2. Seven epitope peptides (n-Sp1, 2, 6, 7, 11, 13, 14) were confirmed to bind with HLA-A2 and potentially be presented by antigen presenting cells to induce host immune responses. Tetramers containing these peptides could interact with specific CD8+ T cells from convalescent COVID-19 patients, and one dominant epitope (n-Sp1) was defined. In addition, these epitopes could activate and generate epitope-specific T cells in vitro, and those activated T cells showed cytotoxicity to target cells. Meanwhile, all these epitopes exhibited high frequency of variations. Among them, n-Sp1 epitope variation 5L>F significantly decreased the proportion of specific T cell activation; n-Sp1 epitope 8L>V variant showed significantly reduced binding to HLA-A2 and decreased the proportion of n-Sp1-specific CD8+ T cell, which potentially contributes to the immune escape of SAR-CoV-2.

immunology↗

bioRxiv2021

The VTA-BLA-NAc circuit for sex reward inhibited by VTA GABAergic neurons under stress in male mice

Anhedonia, inability to experience pleasure from rewarding or enjoyable activities, is the prominent symptom of depression that involves dysfunction of the reward processing system. Both genetic predisposition and life events are thought to increase the risk for depression, in particular life stress. The cellular mechanism underlying stress modulating the reward processing neural circuits and subsequently disrupting reward-related behaviors remains elusive. We identify the VTA-BLA-NAc pathway as being activated by sex reward. Blockade of this circuit induces depressive-like behaviors, while reactivation of VTA neurons associated with sexual rewarding experience acutely ameliorates the impairment of reward-seeking behaviors induced by chronic restraint stress. Our histological and electrophysiological results show that the VTA neuron subpopulation responding to restraint stress inhibits the responsiveness of the VTA dopaminergic neurons to sexual reward. Together, these results reveal the cellular mechanism by which stress influences the brain reward processing system and provide a potential target for depression treatment.

neuroscience↗

bioRxiv2021

Hidden Transcriptome Signature in Autism Spectrum Disorder (ASD) is Attributed to the Interpatient Heterogeneity

Recent studies of ASD have mostly supported the existence of heterogeneity and genomic variation in ASD which have hindered and restrained development of any effective and targetable treatment for a long time. As numerous studies have shown, both genetic and phenotypic heterogeneity is presented in ASD, however, heterogeneity in genetic level is not fully understood which is the key challenges for the further research. Even dozens of ASD susceptibility genes have been discovered which is commonly accounting for 10 to 20 percent of ASD cases, the internal complex combination of mutated genes that determine the epigenetic factors of ASD is still not comprehensively recognized by the recent studies. First by discouraging the traditional method that have been applied in most of the current research of diseases, this research will then focus on dissecting the heterogeneity of polygenic diseases and analyzing with an unconventional approach for acquiring Differently Expressed Genes (DEGs) in Guptas Dataset that provided transcriptome of frontal cortex of ASD patients. Divide categories by using unsupervised learning strategy, the results yielded by analyzing within clusters of ASD have supported the feasibility of the attempts to use heterogeneity to reveal its underlying mechanism. This study puts forward the inference that the heterogeneity of polygenic diseases will obscure the molecular signals related to the disease, and at the same time attempts to use heterogeneity to reveal the underlying mechanism.

bioinformatics↗

bioRxiv2021

A genome wide copper-sensitized screen identifies novel regulators of mitochondrial cytochrome c oxidase activity

Copper is essential for the activity and stability of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Loss-of-function mutations in genes required for copper transport to CcO result in fatal human disorders. Despite the fundamental importance of copper in mitochondrial and organismal physiology, systematic characterization of genes that regulate mitochondrial copper homeostasis is lacking. To identify genes required for mitochondrial copper homeostasis, we performed a genome-wide copper-sensitized screen using DNA barcoded yeast deletion library. Our screen recovered a number of genes known to be involved in cellular copper homeostasis while revealing genes previously not linked to mitochondrial copper biology. These newly identified genes include the subunits of the adaptor protein 3 complex (AP-3) and components of the cellular pH-sensing pathway-Rim20 and Rim21, both of which are known to affect vacuolar function. We find that AP-3 and the Rim mutants impact mitochondrial CcO function by maintaining vacuolar acidity. CcO activity of these mutants could be rescued by either restoring vacuolar pH or by supplementing growth media with additional copper. Consistent with these genetic data, pharmacological inhibition of the vacuolar proton pump leads to decreased mitochondrial copper content and a concomitant decrease in CcO abundance and activity. Taken together, our study uncovered a number of novel genetic regulators of mitochondrial copper homeostasis and provided a mechanism by which vacuolar pH impacts mitochondrial respiration through copper homeostasis.

biochemistry↗

bioRxiv2020

Genomic profiling of cancerous patients identifies FPR2 as an alternative immunotherapeutic target in glioblastoma multiforme

BackgroundGlioblastoma multiforme (GBM) is a type of high-grade brain tumor known for its proliferative, invasive property, and low survival rate. Recently, with the advancement in therapeutics for tumors such as targeted therapy, individual cancer-specific biomarkers could be recognized as targets for curative purposes. This study identified six differentially expressed genes that have shown significant implications in clinical field, including FPR2, VEGFA, SERPINA1, SOX2, PBK, and ITGB3. FPR2 was of the same protein family with FPR1, and the latter has been repeatedly reported to promote motility and invasiveness of multiple tumor forms. MethodsThe gene expression profiling of 40 GBM samples and five normal samples from the TCGA database were comprehensively analyzed. The differentially expressed genes (DEGs) were identified using R package and screened by enrichment analysis and examination of protein-protein interaction networks, in order to further explore the functions of DEGs with the highest association with clinical traits and to find hub genes. A qRT-PCR and Western blots were conducted to verify the results of this study. ResultsOur investigation showed that FPR2, VEGFA, SERPINA1, SOX2, PBK, and ITGB3 were significantly up-regulated in GBM primary tumor compared to the control group. Functional enrichment analysis of the DEGs demonstrated that biological functions related to immune systems, cell division and cell cycle were significantly increased, which were closely related to tumor progression and development. Downstream construction of PPI network analysis indicated that FPR2 was a hub gene involved in high level of interaction with CR3 and VEGFA, which played a key role in inflammatory pathways and cellular dysfunction. ConclusionFPR2, VEGFA, SERPINA1, SOX2, PBK, and ITGB3 were significantly over-expressed in primary tumor samples of GBM patients and were involved in cellular functions and pathways contributing to tumor progression. Out of these six pivotal genes, we intensively focused on FPR2, and our analysis and experimental data both suggested its efficacy as a potential biomarker, serving as an alternative immunotherapeutic target for glioblastoma multiforme.

bioinformatics↗

bioRxiv2020

Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments

The functional interpretation of GWAS remains challenging due to cell-type dependent influences of genetic variants. Here, we generated comprehensive maps of expression quantitative trait loci (eQTL) for 659 microdissected human kidney samples and identified cell-type eQTLs by mapping interactions between cell type abundance and genotype. Separately, we generated single cell open chromatin maps (by snATAC-seq) for human kidney samples. We highlight critical enrichment of proximal tubules in kidney function and endothelial cells and distal tubule segments in blood pressure by partitioning heritability using stratified LD-score regression to integrate GWAS with scRNA-seq and snATAC-seq data. Bayesian colocalization analysis nominated more than 200 genes for kidney function and hypertension. Our study clarifies the mechanism of the most commonly used antihypertensive and renal protective drugs and identifies drug repurposing opportunities for kidney disease. One Sentence SummaryWe define causal cell types, genes and mechanism for kidney dysfunction.

genetics↗