Biology subjects

Graumann, J.

Publications and source records attributed to Graumann, J..

17 recordsLinked to original sources

bioRxiv2026

Cell-specific FUS loss enhances ageing-associated transcriptional elongation in lung fibrosis

Idiopathic pulmonary fibrosis (IPF) is an age-related, lethal lung disease affecting over 3 million people worldwide. During aging, impairment of diverse molecular processes compromises cellular homeostasis. Eukaryotic cells adapt to this ageing-associated stress by large-scale transcriptome changes affecting the expression of genes involved in signaling, protein homeostasis, cell plasticity and immune response. The molecular mechanisms regulating extensive transcriptome rearrangements leading to senescence in specific cell types of IPF lungs remain sparsely investigated. Here we uncover fundamental molecular mechanisms underlying cellular senescence by integrative analysis of multi-omics studies and functional experiments monitoring fibrotic and senescence hallmarks in primary lung fibroblasts from control and IPF patients. Loss-of-function of the DNA/RNA binding protein fused in sarcoma (FUS) in control fibroblasts enhanced fibrotic and senescence hallmarks resembling IPF fibroblasts. Dissecting the molecular mechanisms, reduced FUS levels in IPF fibroblasts abolished R-loop formation at transcription start sites (TSS), leading to increased RNA polymerase II (Pol II) recruitment and its phosphorylation at serine 2, resulting in enhanced translocation speed of elongating Pol II and increased expression of fibrosis- and senescence-related genes. Summarizing, FUS maintains low Pol II processivity in control fibroblasts by stabilizing R-loops at TSS, acting as a gatekeeper of fibrotic and age-associated transcriptional programs.

molecular biology↗

bioRxiv2026

Phosphorylation of the mRNP component Yra1 couples heat stress to nuclear mRNA export inhibition

The ability to adapt to changing environmental conditions is essential for cellular survival. A central feature of the eukaryotic stress response is the inhibition of bulk mRNA nuclear export, while stress-induced transcripts are specifically exported. However, the molecular mechanisms that simultaneously inhibit bulk mRNA export while mediating selective export of specific transcripts remain poorly understood. Here, we performed comparative phosphoproteomic analyses of S. cerevisiae under different stress conditions. We identified a heat shock-induced increase in phosphorylation within the N-terminal domain of the mRNA export adaptor Yra1. Preventing this phosphorylation significantly reduces nuclear accumulation of poly(A)+ RNA during heat stress and concomitantly enhances the export of heat-induced transcripts. Mechanistically, Yra1 phosphorylation appears to weaken its interaction with the export receptor Mex67, thereby contributing to nuclear accumulation of bulk poly(A)+ RNA under heat stress. Together, our findings establish Yra1 phosphorylation as a previously unrecognized regulatory mechanism that promotes nuclear mRNA accumulation during heat stress and contributes to selective mRNA export.

Molecular Biology↗

bioRxiv2025

A microprotein encoded by FERMT3 modulates endothelial cell protein catabolism and induces p53-mediated cell cycle arrest and senescence

BackgroundHuman endothelial cells express numerous microproteins (miPs) encoded by small open reading frames (smORFs) distributed throughout the genome, yet the biological functions of most remain unknown. This study set out to characterize a novel 69 amino acid miP encoded by a smORF located within the coding sequence of the FERM domain containing kindlin-3 transcript (miP-FERMT3). MethodsConfocal microscopy was used to determine the subcellular localization of miP-FERMT3 in endothelial cells and its interaction partners were determined by mass spectrometry and immunoblotting. RNA sequencing identified transcriptional alterations induced by miP-FERMT3 overexpression. Cell proliferation and cell cycle stages were assessed by live cell imaging, EdU incorporation and flow cytometry, while senescence was examined by senescence-associated {beta}-galactosidase staining, live cell imaging and RT-qPCR-based measurement of telomere length. ResultsIn endothelial cells miP-FERMT3 localized mainly to centriole subdistal appendages, where it interacted with proteins involved in ubiquitin- and proteasome-dependent protein catabolism, including PSMD9, CUL2 and TRIM8. Consistent with these interactions, cells expressing miP-FERMT3 exhibited increased global protein ubiquitination, enhanced centrosomal neddylation and elevated proteasomal activity. MiP-FERMT3 also promoted the nuclear accumulation of p53, which subsequently repressed FOXM1 expression, leading to the downregulation of genes required for cell-cycle progression and upregulation of genes involved in cell cycle inhibition, resulting in cell-cycle arrest. Cells expressing the miP also demonstrated multiple hallmarks of cellular senescence, including enlarged size, DNA damage, increased senescence-associated {beta}-galactosidase activity, telomere shortening and paracrine pro-inflammatory activation of naive endothelial cells. Analyses of independent murine and human transcriptomic and proteomic aging datasets further revealed that FERMT3 expression and protein abundance increase with age. ConclusionsThese findings identify miP-FERMT3 as a novel regulator of protein catabolism and p53-dependent cell cycle arrest and cellular senescence in endothelial cells. Given the aging-associated upregulation of FERMT3 in mouse and human endothelial cells, increased miP-FERMT3 expression may contribute to the onset of vascular senescence as a hallmark of aging.

cell biology↗

bioRxiv2025

Microprotein miP-PSTPIP2 affects cytoskeleton dynamics to modulate endothelial cell endocytosis, barrier function and migration

BackgroundA large number of microproteins (miPs) encoded by small open reading frames (smORFs) are expressed in endothelial cells, yet their function remains largely unknown. In this study, we characterized a novel 46-amino-acid miP encoded by a smORF within the proline-serine-threonine phosphatase interacting protein 2 (PSTPIP2) transcript that was upregulated under inflammatory conditions and we refer to as miP-PSTPIP2. MethodsImmunoprecipitation coupled with mass spectrometry-based proteomics, immunoblotting, immunofluorescence and proximity ligation assays were used to identify and validate miP-PSTPIP2 interacting proteins in human endothelial cells. The impact of adenovirus-mediated overexpression of miP-PSTPIP2 on endocytosis, cytoskeleton dynamics and abundance of proteins involved in these processes was investigated by confocal microscopy and immunoblotting. Live cell imaging was used to assess endothelial cell migration and vascular permeability. ResultsmiP-PSTPIP2 physically associated with caveolar proteins, proteins involved in the regulation of cytoskeleton dynamics, intracellular transport, clathrin adaptor activity, as well as nuclear proteins. Human endothelial cells overexpressing miP-PSTPIP2 demonstrated enhanced endocytosis and transcytosis of transferrin as well as low-density lipoprotein. Mechanistically, miP-PSTPIP2 modulated Arp2/3-mediated actin nucleation and branching, which are required for dynamic cytoskeleton rearrangements. Moreover, altered cytoskeleton dynamics in miP-PSTPIP2-expressing endothelial cells resulted in impaired cell migration as well as increased permeability and monocyte trans-endothelial migration. ConclusionsmiP-PSTPIP2 is an inflammation-induced endothelial miP that regulates Arp2/3-dependent actin dynamics, thereby enhancing lipid uptake and leukocyte permeability. Its upregulation under inflammatory conditions suggests a contributory role in endothelial dysfunction and vascular inflammation.

cell biology↗

bioRxiv2025

Immunomodulatory endothelial cells contribute to T cell recruitment and activation through antigen presentation on MHC class II

AimsA subset of endothelial cells referred to as immunomodulatory endothelial cells (IMEC) has been proposed to regulate T cell responses in atherosclerosis, but their phenotype and function remain poorly understood. Here, we characterized the inflammation-induced emergence of IMEC and their crosstalk with T cells. Methods and ResultsAn in vitro model to study IMEC was established and characterized using flow cytometry and proteomics. Single-cell transcriptome data from human atherosclerotic arteries as well as single cell transcriptome and endothelial cell-specific translatome data from a murine atherogenesis model were used to determine pathophysiological relevance. Immunopeptidomics was performed to detect antigen presentation. T cell chemotaxis, adhesion and activation were assessed through flow cytometry and microscopy. IMEC were induced by treating human endothelial cells with interleukin-1{beta}, interferon-{gamma}, and transforming growth factor-{beta}2. These cells expressed lower levels of classical endothelial cell markers but expressed major histocompatibility complex (MHC) class II, proteins involved in antigen processing and presentation (CD83, CD80 and CD86) and pro-inflammatory cytokines as well as chemokines, including CXCL9. An endothelial cell subpopulation with similar immunomodulatory features was identified in a mouse model of accelerated atherogenesis as well as in human atheromas. Conditioned medium from IMEC enhanced the migration of peripheral blood mononuclear cells and induced T cell chemotaxis, the latter being partially inhibited by antagonizing CXCL9. Proteins related to glycosaminoglycan degradation were significantly downregulated in IMEC which was relevant inasmuch as the glycocalyx plays a key role in the establishment of chemokine gradients. Indeed, the accumulation of heparan sulfates in IMEC contributed to the adhesion of T cells. Notably, IMEC that had been exposed to monocyte lysates presented 627 peptide antigens on MHC class II and induced T cell activation. ConclusionOur data demonstrate the role of IMEC as non-professional antigen-presenting cells that potentially contribute to T cell-mediated immune responses in cardiovascular disease. Translational PerspectiveThis study characterizes immunomodulatory endothelial cells (IMEC) as critical mediators of vascular inflammation through their capacity to process and present exogenous antigens and activate T cells. Induced by pro-atherogenic cytokines (IFN-{gamma}, IL-1{beta}, TGF-{beta}2), IMEC upregulate MHC class II and costimulatory molecules, promote leukocyte chemotaxis, and enhance T cell adhesion through surface heparan sulfate. The identification of IMEC-like populations in both murine models and human atherosclerotic plaques indicates a conserved immunological function in atherogenesis. These findings position IMEC as novel, non-professional antigen-presenting cells and potential therapeutic targets to modulate vascular immune responses in atherosclerotic cardiovascular disease.

immunology↗

bioRxiv2025

Erlotinib induces 3D genome rearrangements in lung cancer cells activating tumor suppressor genes through FOXA2-bound Epromoters

Non-small cell lung cancer (NSCLC) is the most frequent lung cancer (LC). While erlotinib is an epidermal growth factor (EGFR) tyrosine kinase inhibitor (TKI) used in the treatment of NSCLC, it remains unclear how this FDA-approved drug affects the genome. We performed integrative multi-omics studies in human pulmonary carcinoma cells to elucidate the epigenetic mechanisms induced by erlotinib. We identified 746 genes (including 34 tumor suppressor genes, TSG) that were upregulated after treatment with erlotinib or gefitinib (another EGFR-TKI). Interestingly, 45% of the upregulated genes (including 24 TSG) were in broad domains of the euchromatin histone mark H3K4me3, and 63% (including 26 TSG) exhibited reduced levels of the heterochromatin histone mark H3K27me3 after erlotinib treament. Further, H3K27ac-specific chromosome conformation capture-based methods revealed that erlotinib significantly increased number and length of chromatin loops between promoters of upregulated genes and active enhancers. We also detected augmented chromatin accessibility after erlotinib treatment at the promoters of upregulated genes, which correlated with binding of the transcription activator FOXA2. Remarkably, we identified gene clusters that seem to be upregulated by promoters with enhancer activity (Epromoters) enriched with FOXA2. The clinical relevance of our findings was confirmed by data from The Cancer Genome Atlas, showing significantly improved survival outcomes in LC patients with high levels of FOXA2 and/or the 34 TSG found upregulated by erlotinib. Our results establish 3D genome rearrangements as molecular mechanism mediating EGFR-TKI effects in NSCLC cells, supporting the design of more specific therapies for NSCLC targeting different chromatin features.

cancer biology↗

bioRxiv2025

Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes

As cancer cell specific rewiring of metabolic networks creates potential therapeutic opportunities, we conducted a synthetic lethal screen utilizing inhibitors of metabolic pathways. Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells. While (R)-GNE-140 inhibits lactate dehydrogenase (LDH)A/B and thus effective glycolysis, BMS-986205, in addition to its known inhibitory activity on Indoleamine 2,3-dioxygenase (IDO1), also restricts oxidative phosphorylation (OXPHOS), as revealed here. BMS-986205, which is being tested in multiple Phase III clinical trials, inhibits the ubiquinone reduction site of respiratory complex I and thus compromises mitochondrial ATP production. The energetic catastrophe caused by simultaneous interference with glycolysis and OXPHOS resulted in either cell death or the induction of senescence in tumor cells, with the latter being eliminated by senolytics. The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention.

cancer biology↗

bioRxiv2022

Extracellular vesicles induce aggressive lung cancervia non-canonical integrin-EGFR-KRAS signaling

Small cell lung cancer (SCLC) is an extremely aggressive lung cancer type with a patient median survival of 6-12 months. Epidermal growth factor (EGF) signaling plays an important role in triggering SCLC. In addition, growth factor-dependent signals and alpha-, beta-integrin (ITGA, ITGB) heterodimer receptors functionally cooperate and integrate their signaling pathways. However, the precise role of integrins in EGF receptor (EGFR) activation in SCLC has remained elusive. We analyzed RNA-sequencing data, human precision-cut lung slices (hPCLS), retrospectively collected human lung tissue samples and cell lines to demonstrate that non-canonical ITGB2 signaling activates EGFR and RAS/MAPK/ERK signaling in SCLC. Further, we identified a novel SCLC gene expression signature consisting of 93 transcripts that were induced by ITGB2, which might be used for stratification of SCLC patients, prognosis prediction of LC patients and development of patient-tailored therapies. We also found by proteomic analysis a cell-cell communication mechanism based on extracellular vesicles (EVs) containing ITGB2, which were secreted by SCLC cells and induced in control human lung tissue RAS/MAPK/ERK signaling and SCLC markers. We uncovered a mechanism of ITGB2-mediated EGFR activation in SCLC that explains EGFR-inhibitor resistance independently of EGFR mutations, suggesting the development of therapies targeting ITGB2 for patients with this extremely aggressive lung cancer type.

cancer biology↗

bioRxiv2020

Depletion of cardiolipin induces major changes in energy metabolism in Trypanosoma brucei bloodstream forms

Cardiolipin (CL) is a mitochondrial inner membrane glycerophospholipid that associates with mitochondrial proteins to promote their activities and to facilitate protein complex and super-complex formation. Loss of CL leads to destabilized respiratory complexes and mitochondrial dysfunction. The role of CL in an organism lacking a conventional electron transport chain (ETC) has not been elucidated so far. We now report that in Trypanosoma brucei bloodstream forms, in which the ETC is truncated and composed of alternative oxidase and glycerol-3-phosphate dehydrogenase, and the mitochondrial membrane potential is generated by the hydrolytic action of the FoF1-ATP synthase, the inducible depletion of cardiolipin synthase (TbCls) is essential for parasite survival. Loss of TbCls and CL caused a rapid drop in ATP levels and a decline in the mitochondrial membrane potential. Unbiased proteomic analyses revealed a reduction in the levels of many mitochondrial proteins, most notably of FoF1-ATP synthase subunits and of the alternative oxidase, resulting in a strong decline of glycerol-3-phosphate-stimulated oxygen consumption. Interestingly, the changes in cellular respiration preceded the observed decrease in FoF1-ATPase stability, suggesting that the truncated ETC is the first pathway responding to the decline in CL. In addition, proteomic and metabolomic analyses revealed that select proteins and pathways involved in glucose and amino acid transport and metabolism are up-regulated during CL depletion, possibly as a stress response to restore cellular ATP levels.

biochemistry↗

bioRxiv2020

multicrispr: fast gRNA designer enables prime editing and parallel targeting of thousands of targets

Targeting the coding genome to introduce single nucleotide deletions/insertions via Crispr/Cas9 technology has become a standard procedure in recent years. It has quickly spawned a multitude of methods such as Prime Editing, Crispr/Cas9 assisted APEX proximity labeling of proteins, or homology directed repair (HDR), for which supporting bioinformatic tools are, however, lagging behind. New applications often require specific guide-RNA (gRNA) design functionality, and a generic gRNA design tool is critically missing. Here we review gRNA designer software and introduce multicrispr, an R based tool intended to design individual gRNAs as well as gRNA libraries targeting many genomic loci in parallel. The package is easy to use, detects, scores and filters gRNAs on both efficiency and specificity, visualizes and aggregates results per target or Crispr/Cas9 sequence, and finally returns both genomic ranges as well as sequences of preferred, off target-free gRNAs. In order to be generic, multicrispr defines and implements a genomic arithmetics framework as a basis for facile adaptation to techniques yet to arise. Its performance and new gRNA design concepts such as target set specific filtering for gRNA libraries render multicrispr the tool of choice when dealing with screening-like approaches.

bioinformatics↗

bioRxiv2020

On identifying the eukaryotic N-glycosylation scramblase by activity correlation profiling

The canonical pathway of N-linked protein glycosylation in yeast and humans involves transfer of the oligosaccharide moiety from the glycolipid Glc3Man9GlcNAc2-PP-dolichol to select asparagine residues in proteins that have been translocated into the lumen of the endoplasmic reticulum (ER). Synthesis of Glc3Man9GlcNAc2-PP-dolichol occurs in two stages, producing first the key intermediate Man5GlcNAc2-PP-dolichol (M5-DLO) on the cytoplasmic face of the ER, followed by translocation of M5-DLO across the ER membrane to the luminal leaflet where the remaining glycosyltransfer reactions occur to complete the structure. Despite its critical importance for N-glycosylation, the scramblase protein that mediates the translocation of M5-DLO across the ER membrane has not been identified. Building on our ability to recapitulate scramblase activity in large unilamellar proteoliposomes reconstituted with a crude mixture of ER membrane proteins, we developed a mass spectrometry-based activity correlation profiling approach to identify scramblase candidates in the yeast Saccharomyces cerevisiae. Curation of the activity correlation profiling data prioritized six polytopic ER membrane proteins as scramblase candidates, but reconstitution-based assays and gene disruption in the protist Trypanosoma brucei revealed, unexpectedly, that none of these proteins were necessary for M5-DLO scramblase activity. Our results instead suggest the possibility that the M5-DLO scramblase may be a protein, or protein complex, whose activity is regulated at the level of quaternary structure. This key insight will aid future attempts to identify the scramblase.

biochemistry↗

bioRxiv2020

Insulin promoted mobilization of GLUT4 from a perinuclear storage site requires RAB10.

Insulin controls glucose uptake into muscle and fat cells by inducing a net redistribution of GLUT4 from intracellular storage to the plasma membrane (PM). The TBC1D4-RAB10 signaling module is required for insulin-stimulated GLUT4 translocation to the PM, although where it intersects GLUT4 traffic was unknown. Here we demonstrate that TBC1D4-RAB10 functions to control GLUT4 mobilization from a Trans Golgi Network (TGN) storage compartment, establishing that insulin, in addition to regulating the PM proximal effects of GLUT4-containing vesicles docking to and fusion with the PM, also directly regulates the behavior of GLUT4 deeper within the cell. We also show that GLUT4 is retained in an element/domain of the TGN from which newly synthesized lysosomal proteins are targeted to the late endosomes and the ATP7A copper transporter is translocated to the PM by elevated copper. Insulin does not mobilize ATP7A nor does copper mobilize GLUT4. Consequently, GLUT4 intracellular sequestration and mobilization by insulin is achieved, in part, through utilizing a region of the TGN devoted to specialized cargo transport in general rather than being specific for GLUT4. Our results define GLUT4-containing region of the TGN as a sorting and storage site from which different cargo are mobilized by distinct signals.

cell biology↗

bioRxiv2020

Positioning of nucleosomes containing γ-H2AXprecedes active DNA demethylation and transcription initiation

In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of HMG proteins during transcription initiation remain unclear. Here we show that HMG AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT (facilitates chromatin transcription) complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 ({gamma}-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure the integrity of the genome.

molecular biology↗

bioRxiv2018

Screening for insulin-independent pathways that modulate glucose homeostasis identifies androgen receptor antagonists

Pathways modulating glucose homeostasis independently of insulin would open new avenues to combat insulin resistance and diabetes. Here, we report the establishment, characterization and employment of a vertebrate insulin-free model to identify insulin-independent modulators of glucose metabolism. insulin knockout zebrafish recapitulate core characteristics of diabetes and survive only up to larval stages. Utilizing a highly efficient endoderm transplant technique, we generated viable chimeric adults that provide the large numbers of insulin mutant larvae required for our screening platform. Using glucose as a disease-relevant readout, we screened 2233 molecules and identified 3 that consistently reduced glucose levels in insulin mutants. Most significantly, we uncovered an insulin-independent beneficial role for androgen receptor antagonism in hyperglycemia, mostly by reducing fasting glucose levels. Our study proposes therapeutic roles for androgen signaling in diabetes and, more broadly, offers a novel in vivo model for rapid screening and decoupling of insulin-dependent and -independent mechanisms.

developmental biology↗

bioRxiv2018

Myh10 deficiency leads to defective extracellular matrix remodeling and pulmonary disease

Impaired alveolar formation and maintenance are features of many pulmonary diseases that are associated with significant morbidity and mortality. In a forward genetic screen for modulators of mouse lung development, we identified the non-muscle myosin II heavy chain gene, Myh10. Myh10 mutant pups exhibit cyanosis and respiratory distress, and die shortly after birth from differentiation defects in alveolar epithelium and mesenchyme. From omics analyses and follow up studies, we find decreased Thrombospondin expression accompanied with increased matrix metalloproteinase activity in both mutant lungs and cultured mutant fibroblasts, as well as disrupted extracellular matrix (ECM) remodeling. Loss of Myh10 specifically in mesenchymal cells results in ECM deposition defects and alveolar simplification. Notably, MYH10 expression is down-regulated in the lung of emphysema patients. Altogether, our findings reveal critical roles for Myh10 in alveologenesis at least in part via the regulation of ECM remodeling, which may contribute to the pathogenesis of emphysema.

developmental biology↗

bioRxiv2017

Genome-wide Association Study Of Plasma Proteins Identifies Putatively Causal Genes, Proteins, And Pathways For Cardiovascular Disease

Identifying genetic variants associated with circulating protein concentrations (pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteomes causal role in disease and bridge a GWAS knowledge gap for hitherto unexplained SNP-disease associations. We conducted GWAS of 71 high-value proteins for cardiovascular disease in 6,861 Framingham Heart Study participants followed by external replication. We comprehensively mapped thousands of pQTLs, including functional annotations and clinical-trait associations, and created an integrated plasma-protein-QTL searchable database. We next identified 15 proteins with pQTLs coinciding with coronary heart disease (CHD)-related variants from GWAS or tested causal for CHD by Mendelian randomization; most of these proteins were associated with new-onset cardiovascular disease events in Framingham participants with long-term follow-up. Identifying pQTLs and integrating them with GWAS results yields insights into genes, proteins, and pathways that may be causally associated with disease and can serve as therapeutic targets for treatment and prevention.

epidemiology↗

bioRxiv2016

Connecting genetic risk to disease endpoints through the human blood plasma proteome

Genome-wide association studies (GWAS) with intermediate phenotypes, like changes in metabolite and protein levels, provide functional evidence for mapping disease associations and translating them into clinical applications. However, although hundreds of genetic risk variants have been associated with complex disorders, the underlying molecular pathways often remain elusive. Associations with intermediate traits across multiple chromosome locations are key in establishing functional links between GWAS-identified risk-variants and disease endpoints. Here, we describe a GWAS performed with a highly multiplexed aptamer-based affinity proteomics platform. We quantified associations between protein level changes and gene variants in a German cohort and replicated this GWAS in an Arab/Asian cohort. We identified many independent, SNP-protein associations, which represent novel, inter-chromosomal links, related to autoimmune disorders, Alzheimer's disease, cardiovascular disease, cancer, and many other disease endpoints. We integrated this information into a genome-proteome network, and created an interactive web-tool for interrogations. Our results provide a basis for new approaches to pharmaceutical and diagnostic applications.

genetics↗