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PubMed2026

Human Variation-Informed Prioritization of MPHOSPH6 in Lung Adenocarcinoma: A Source-Aware Multiomics Evidence Framework.

Moving from an association signal to a clinically credible biomarker requires several links that are often conflated: verified variant identity, aligned allelic effects, reproducible gene-level association, relevant cellular expression, and a plausible functional consequence. We developed a source-aware multiomics framework to assess MPHOSPH6 in lung adenocarcinoma (LUAD) while keeping those evidence classes separate. Six prespecified rsIDs were recovered from the harmonized TRICL LUAD dataset, of which five reached p < 5 × 10 - 8. Only rs112333466 and rs76474922 were available with alignable alleles in FinnGen R10, and both showed concordant directions. Fixed-effect estimates were OR = 1.592 for rs112333466-T (95% CI, 1.401-1.809; p = 9.91 × 10 - 13) and OR = 0.819 for rs76474922-C (95% CI, 0.773-0.867; p = 1.03 × 10 - 11). In a prespecified two-variant GTEx v8 lung model, genetically predicted MPHOSPH6 expression was positively associated with LUAD in TRICL (Z = 3.341, p = 8.35 × 10 - 4) and FinnGen (Z = 2.697, p = 0.0070). This gene-level result did not establish colocalization or connect MPHOSPH6 to the six susceptibility rsIDs. Patient-level analysis of 89,241 immune cells from six paired tumor and normal-adjacent lung samples found no significant difference in MPHOSPH6 pseudobulk abundance (exact paired Wilcoxon p = 0.3125). None of 688 lung-lineage pharmacogenomic tests remained significant after false-discovery-rate correction. Ten recorded MPHOSPH6 missense alleles, including five ClinVar variants of uncertain significance, were curated; structural analysis identified I58 at an experimental RNA-exosome interface and defined a focused perturbation series. MPHOSPH6 is therefore supported as a human-variation-informed candidate for functional evaluation, not as a validated LUAD biomarker, pathogenic gene, drug-response predictor, or therapeutic target.

Humans↗

PubMed1991

Biochemical and morphological analysis of the interaction of epidermal growth factor and parathyroid hormone with UMR 106 osteosarcoma cells.

The interaction of epidermal growth factor (EGF) and PTH with UMR 106 osteosarcoma cells was examined biochemically and morphologically. EGF inhibited PTH-stimulated adenylate cyclase activity in association with a reduction in PTH receptors and a decrease in the activity of the stimulatory guanyl nucleotide-binding protein (Gs). Universal inhibition of agonist-stimulated adenylate cyclase activity did not occur, inasmuch as EGF did not reduce prostaglandin E2-enhanced enzyme activity. The influence of EGF on PTH action correlated with its effect in the UMR 106 cell population of promoting entry into the cell cycle. Morphological analysis with radioautography indicated that both EGF and PTH receptors could be colocalized to certain UMR 106 cells, but that each were more abundantly distributed over discrete UMR 106 cell types. Based on the distribution of [3H]thymidine incorporation, EGF receptors were predominantly found over rapidly proliferating cells, whereas PTH receptors were most densely distributed over more quiescent cells. The results indicate that EGF and PTH receptors are localized over specific types within the heterogeneous population of UMR 106 cells and suggest that EGF may reduce PTH action in these cultures by enhancing the proliferation of progenitor cells lacking PTH receptors and reducing differentiation in this cell population, which leads to PTH receptor-enriched target cells. EGF and PTH receptors may, therefore, be useful as probes to examine both functional interactions and differentiation pathways among cells in osteoblast models in vitro and perhaps in vivo.

Adenylyl Cyclase Inhibitors↗

PubMed1991

Differential effect of functional olfactory bulb deafferentation on tyrosine hydroxylase and glutamic acid decarboxylase messenger RNA levels in rodent juxtaglomerular neurons.

Expression of the dopaminergic phenotype in olfactory bulb (OB) juxtaglomerular neurons (constituting a population of periglomerular and external tufted cells) is dependent upon functional innervation by peripheral olfactory receptors. Loss of functional input in rodents, by either peripheral deafferentation or deprivation of odorant access, results in a profound decrease in the expression of juxtaglomerular tyrosine hydroxylase (TH). We have examined the effects of such treatments on the expression of the neurotransmitter biosynthetic enzyme glutamic acid decarboxylase (GAD), which is colocalized with TH in the majority of TH-containing juxtaglomerular neurons. Following either chemically induced OB deafferentation in adult mice or unilateral odor deprivation in neonatal rats, steady-state OB GAD messenger RNA levels remained essentially unchanged as assessed by Northern blot analysis 20-40 days after treatment. These results were confirmed by in situ hybridization analysis, which demonstrated a profound loss of juxtaglomerular TH messenger RNA but no accompanying decrease in regionally colocalized GAD message. Since GAD is found in nearly all dopaminergic OB cells, the preservation of juxtaglomerular GAD message implies that olfactory receptor neurons exert a differential transneuronal regulation of TH and GAD gene transcription.

Animals↗

PubMed1992

An autosomal homologue of the choroideremia gene colocalizes with the Usher syndrome type II locus on the distal part of chromosome 1q.

Employing the mouse homologue of the human choroideremia cDNA as a probe, we have identified a homologous human gene. The consensus cDNA of this gene, designated human choroideremia-like (hCHML) gene, encompasses an open reading frame of 1968 base pairs. The deduced polypeptide of hCHML displays several regions of homology to smg p25A GDI, a bovine protein known to regulate the GDP/GTP exchange of the GTP-binding protein smg p25A. hCHML is located at 1q31-qter, a chromosomal region which, by means of linkage analysis, was previously shown to carry a gene locus for Usher syndrome type II. The colocalization of hCHML and Usher syndrome type II, as well as the clinical similarities between choroideremia and Usher syndrome type II, make hCHML a candidate gene for this disorder.

Amino Acid Sequence↗

PubMed1991

Characterization of the distribution of G alpha o in rat striatal synaptosomes and its colocalization with tyrosine hydroxylase.

Dopaminergic striatal synaptosomes can be detected and isolated with a fluorescence-activated cell sorter (FACS). In the present study, two antigens were detected simultaneously with primary antisera raised in different species and species-specific fluorescent secondary antibodies with different emission spectra. Double-label FACS analysis was used to determine whether tyrosine hydroxylase (TH) and the alpha subunit of Go (G alpha o) are colocalized in striatal synaptosomes. Rabbit antibodies generated against a synthetic fragment of G alpha o (corresponding to amino acids 22-35) combined with fluorescein-conjugated secondary antibodies were used to detect G alpha o-containing striatal synaptosomes. Preadsorption of G alpha o antiserum with the synthetic peptide antigen reduced labeling to the level obtained with preimmune serum. Approximately 65-75% of striatal synaptosomes were specifically labeled by G alpha o antiserum. Tyrosine hydroxylase-containing synaptosomes were detected with a mouse monoclonal antibody to TH and R-phycoerythrin-conjugated secondary antibody. They comprised 15-17% of total striatal synaptosomes. Double-label studies indicated that at least 50% of TH-containing synaptosomes also contained G alpha o. These findings suggest that G alpha o may not be a protein component of all striatal nerve terminals, and provide a basis for a role for G alpha o in signal transduction within subpopulations of intrinsic and afferent nerve terminals, including those of nigrostriatal dopamine neurons.

Animals↗

PubMed1992

Simultaneous mobilization of Mac-1 (CD11b/CD18) and formyl peptide chemoattractant receptors in human neutrophils.

Mobilization of a distinct subset of specific granules provides a physiologically important mechanism to recruit Mac-1 (CD11b/CD18) from an intracellular pool to the external surface of the neutrophil plasma membrane, where the functionally active heterodimer mediates several adherence-dependent processes that are crucial for adequate host defense and cellular inflammatory responses. We observed similar characteristics for translocation of Mac-1 and neutrophil formyl peptide receptors (FPR) and hypothesize that the readily accessible pools of both Mac-1 and FPR are colocalized within this specific granule subset. Plasma membrane levels of both FPR (assessed with 3H-FMLP) and Mac-1 (assessed by fluorescence-activated cell sorter analysis of fluorescein isothiocyanate [FITC]-Mo-1-labeled cells) were markedly downregulated in cells prepared at low temperature from blood cooled to 4 degrees C immediately after removal from the circulation. Levels of both FPR and Mac-1 remained low on cells held at 4 degrees C. Upon warming, spontaneous upregulation of Mac-1 and FPR occurred with similar kinetics and temperature dependency. Translocation of both Mac-1 and FPR was markedly potentiated by exposure of cells to either fluoride ion (which has been shown by others to specifically elicit exocytosis of gelatinase-rich and vitamin B-12 binding protein-poor granules) or granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that markedly potentiates the neutrophils' host defense capabilities. Levels of both FPR and Mac-1 on F-- or GM-CSF-treated neutrophils exceeded those present on cells incubated at 37 degrees C for extended time intervals, indicating that stimulated translocation may involve mobilization of an additional granule subset. Scatchard analysis showed that only low-affinity FPR were translocated during spontaneous and stimulus-dependent upregulation. To directly compare FPR levels on the surface of cells displaying varying levels of Mac-1 within a single cell suspension, cells were labeled with FITC-Mo-1 and sorted into subpopulations based on fluorescence intensity. After sorting, the individual populations were held at 4 degrees C to prevent further spontaneous upregulation, concentrated by centrifugation, and assayed for FPR levels. Under a variety of conditions, FPR levels correlated with Mac-1 (CD11b) expression on cell populations selected on the basis of CD11b fluorescence intensity. Analysis of subcellular fractions obtained from disrupted neutrophils before and after upregulation provided additional support for the hypothesis that Mac-1 and FPR are colocalized within a readily accessible subset of neutrophil granules.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Membrane↗

PubMed1991

Sequential rearrangement and nuclear polymerization of actin in baculovirus-infected Spodoptera frugiperda cells.

Proper assembly of nucleocapsids of the baculovirus Autographa californica nuclear polyhedrosis virus is prevented by cytochalasin D, a drug that interferes with actin microfilament function. To investigate the involvement of microfilaments in A. californica nuclear polyhedrosis virus replication, a fluorescence microscopy study was conducted that correlated changes in distribution of microfilaments with events in the life cycle of the virus. Tetramethylrhodamine isothiocyanate-labeled phalloidin was used to label microfilaments, and monoclonal antibody was used to label p39, the major viral capsid protein. Three microfilament arrangements were found in infected cells. During uptake of virus, thick cables were formed. These were insensitive to cycloheximide, indicating that this configuration was a rearrangement of preexisting cellular actin mediated by a component of the viral inoculum. At the time of cell rounding and before viral DNA replication, ventral aggregates of actin were observed. These were sensitive to cycloheximide but not to aphidicolin, indicating that an early viral gene mediated this actin rearrangement. Ventral aggregates did not result from the rounding process itself. Uninfected cells prerounded with colchicine did not form ventral aggregates. Cells prerounded with colchicine and then infected did form aggregates. At the time of exponential production of progency virus, microfilaments were found in the nucleus surrounding the virogenic stroma. In this area (where nucleocapsid assembly is known to take place) microfilaments colocalized with p39. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western immunoblot analysis identified p39 among proteins retained on an f-actin affinity column. We postulate that microfilaments in the nucleus provide a scaffold to position capsids for proper assembly and filling with DNA.

Actin Cytoskeleton↗

PubMed1992

Polysialic acid is associated with sodium channels and the neural cell adhesion molecule N-CAM in adult rat brain.

We have studied alpha 2,8-linked polysialic acid (polySia) and the neural cell adhesion molecule (N-CAM) in the adult rat brain by immunohistochemistry and Western blot analysis. Both molecules were widely distributed but not ubiquitous. Various brain regions showed colocalization of polySia and N-CAM. Strong immunoreactivity for polySia was seen in regions which were negative for N-CAM, such as the main and accessory olfactory bulbs. Immunohistochemical evidence for the heterogeneity of polySia expression in different brain regions was confirmed by immunoblotting. We present evidence that N-CAM is not the only polySia bearing protein in adult rat brain. Specifically, immunoprecipitation using the polySia-specific monoclonal antibody mAb 735 precipitated not only N-CAM isoforms carrying polySia, but also the sodium channel alpha subunit. Immunoblotting using sodium channel alpha subunit antibody (SP20) revealed a smear from 250 kDa upwards. PolySia removal using an endoneuraminidase specific for alpha 2,8-linked polysialic acid of 8 or more residues long, reduced this smear to a single band at 250 kDa. Thus both N-CAM and sodium channels carry homopolymers of alpha 2,8-linked polysialic acid in adult rat brain.

Animals↗

PubMed1991

Incorporation of circulating fibronectin into various tissues during sepsis: colocalization with endogenous tissue fibronectin.

We studied the plasma clearance and tissue incorporation of intravenously infused purified human plasma fibronectin into various tissues during a period of acute lung vascular injury induced by lethal postoperative bacteremia in sheep. Lung, liver, spleen, and heart tissue were examined for both endogenous sheep tissue fibronectin as well as the experimentally infused human fibronectin using dual-label immunofluorescence. Awake sheep (n = 4) received a postoperative iv infusion of 5 x 10(9) live Pseudomonas over a 60-min infusion interval. Bacterial challenge was started 2 hr after starting the iv fibronectin infusion of purified human plasma fibronectin (100 mg iv bolus; 4 hr iv at 100 mg/hr). Human fibronectin displayed a biphasic rate of clearance from the plasma with entrance into lymph. Human fibronectin readily incorporated in all tissues studied, including the lung which was the focus of vascular injury. Analysis of tissue sections by dual-label immunofluorescence indicated that the exogenous human fibronectin colocalized with the endogenous sheep fibronectin. Thus, the plasma fibronectin concentration may influence the lung vascular barrier due to its incorporation into the tissue pool of fibronectin. Moreover, the plasma may serve as a reservoir for soluble fibronectin which can enter and colocalize with the insoluble tissue pool of fibronectin in various tissues.

Animals↗

PubMed1991

A quantitative model suggests immune memory involves the colocalization of B and Th cells.

A prominent and essential feature of the humoral immune response of vertebrates is immunologic memory: the ability to recall previous exposure to antigen. We present a mathematical model of the growth and interactions of the major cell populations involved in the humoral immune response. Our analysis of this model predicts that the formation of a dynamic association between small numbers of antigen-specific B and Th cells, "colocalization", is sufficient to account for memory and the kinetics of the secondary response--neither specifically differentiated Th or B memory cells nor networks of antigen and anti-idiotypes are required. The colocalization hypothesis explains a number of existing experimental observations and can be tested by straightforward experiments which we describe.

Animals↗

PubMed1990

Negative regulation of the rat stromelysin gene promoter by retinoic acid is mediated by an AP1 binding site.

Stromelysin is a member of the metalloproteinase family which plays an important role in extracellular matrix remodelling during many normal and disease processes. We show here that in polyomavirus-transformed rat embryo fibroblast cells (PyT21), the transcription from the stromelysin gene is repressed by the vitamin A derivative retinoic acid (RA). Furthermore, expression vectors encoding the human RA receptors hRAR-alpha, hRAR-beta and hRAR-gamma repress chloramphenicol acetyltransferase (CAT) expression from stromelysin promoter-CAT gene expression vectors in RA-treated PyT21 and human HeLa cells, as determined by transient transfection assays. Through mutation and deletion analysis, we show that the RA dependent repression is mediated by a 25 bp region from nucleotide positions -72 to -48 of the rat stromelysin 5'-flanking DNA sequence. Further mutation analysis of this region indicates that the DNA sequence required for RA dependent repression colocalizes with an AP1 binding site which is essential for promoter activity. We show also that RA represses the transcriptional activity of a reporter gene containing a TPA responding AP1 binding site driving the HSV tk promoter. Thus the RAR-RA complex appears to repress transcription of the stromelysin gene by blocking activation by positive regulatory factors. However, we found no evidence supporting the possibility that the RA dependent repression could be due to RAR binding to the AP1 binding site or to the AP1 components c-fos and c-jun.

Animals↗

PubMed1991

Ability of the c-mos product to associate with and phosphorylate tubulin.

The mos proto-oncogene product, pp39mos, is a protein kinase and has been equated with cytostatic factor (CSF), an activity in unfertilized eggs that is thought to be responsible for the arrest of meiosis at metaphase II. The biochemical properties and potential substrates of pp39mos were examined in unfertilized eggs and in transformed cells in order to study how the protein functions both as CSF and in transformation. The pp39mos protein associated with polymers under conditions that favor tubulin oligomerization and was present in an approximately 500-kilodalton "core" complex under conditions that favor depolymerization. beta-Tubulin was preferentially coprecipitated in pp39mos immunoprecipitates and was the major phosphorylated product in a pp39mos-dependent immune complex kinase assay. Immunofluorescence analysis of NIH 3T3 cells transformed with Xenopus c-mos showed that pp39mos colocalizes with tubulin in the spindle during metaphase and in the midbody and asters during telophase. Disruption of microtubules with nocodazole affected tubulin and pp39mos organization in the same way. It therefore appears that pp39mos is a tubulin-associated protein kinase and may thus participate in the modification of microtubules and contribute to the formation of the spindle. This activity expressed during interphase in somatic cells may be responsible for the transforming activity of pp39mos.

Amino Acid Sequence↗

PubMed1988

Distribution of acetylated alpha-tubulin in retina and in vitro-assembled microtubules.

We have used the mouse monoclonal antibody 6-11 B-1, specific for acetylated alpha-tubulin, to determine the distribution of acetylated alpha-tubulin in in vitro-assembled microtubules and retinal tissue. Analysis by immunoblots revealed that microtubules assembled from bovine brain extracts contain both acetylated and nonacetylated alpha-tubulin. Immunofluorescence, using 6-11 B-1 and antitubulin B-5-1-2, a monoclonal antibody specific for alpha-tubulin, demonstrated the colocalization of both alpha-tubulin species in neurons of the retina and that acetylated microtubules are relatively abundant in neurons. However, analysis at higher resolution revealed that rod photoreceptors contain spatially distinct microtubule arrays which differ in content of acetylated alpha-tubulin and differ in stability. Acetylated microtubules which composed those of the rod outer segment and connecting cilium were resistant to depolymerization in nocodazole or colchicine. In contrast, the nonacetylated microtubules which composed those of the rod-inner segment were depolymerized in nocodazole or colchicine. Therefore, these acetylated microtubules are more resistant to depolymerization than non-acetylated microtubules.

Acetylation↗

PubMed1991

Identification and characterization of a novel cytoskeleton-associated pp60src substrate.

Transformation of cells by the src oncogene results in elevated tyrosine phosphorylation of two related proteins, p80 and p85 (p80/85). Immunostaining with specific monoclonal antibodies revealed a striking change of subcellular localization of p80/85 in src-transformed cells. p80/85 colocalizes with F-actin in peripheral extensions of normal cells and rosettes (podosomes) of src-transformed cells. Sequence analysis of cDNA clones encoding p80/85 revealed an amino-terminal domain composed of six copies of a direct tandem repeat, each repeat containing 37 amino acids, a carboxyl-terminal SH3 domain, and an interdomain region composed of a highly charged acidic region and a region rich in proline, serine, and threonine. The multidomain structure of p80/85 and its colocalization with F-actin in normal and src-transformed cells suggest that these proteins may associate with components of the cytoskeleton and contribute to organization of cell structure.

Amino Acid Sequence↗

PubMed1990

Plasmalemmal vesicles are involved in transendothelial transport of albumin, lysosomal enzymes and mannose 6-phosphate receptor fragments in capillary endothelium.

With the use of immunoelectron microscopy we have demonstrated the presence of lysosomal enzymes (acid alpha-glucosidase and glucocerebrosidase) and fragments of the 270 kDa receptor for mannose 6-phosphate and insulin-like growth factor II in blood plasma, plasmalemmal vesicles of endothelial cells and pericapillary spaces in human skeletal muscle tissue. At these locations, the three proteins colocalized with albumin known to be transported from the capillaries into the pericapillary spaces. Immunoblot analysis of plasma revealed the presence of relatively high molecular weight polypeptides in this material. These observations strongly suggest that high molecular weight species of lysosomal enzymes can pass the endothelial barrier in skeletal muscle tissue.

Albumins↗

PubMed1992

Subcellular distribution of the Rap1A protein in human neutrophils: colocalization and cotranslocation with cytochrome b559.

Rap1A, a low molecular weight guanosine triphosphate-binding protein (LMWG), has been shown previously by us to be associated with purified cytochrome b from stimulated human neutrophils. In the present studies, we show that Rap1A is also associated with affinity-purified cytochrome b from unstimulated neutrophils and use specific anti-Rap1 peptide antibodies to biochemically and immunocytochemically determine the subcellular distribution of Rap1A in resting and activated human neutrophils. Analysis of the subcellular fractionation of unstimulated cells by Western blotting of isopycnic sucrose density gradient fractions with anti-Rap1 peptide antibodies indicated that Rap1A colocalized with cytochrome b in the plasma membrane as well as in the specific granule membranes and that it was translocated, along with cytochrome b, to the plasma membrane when the cells were stimulated with phorbol myristate acetate (PMA). No evidence for a cytosolic localization of Rap1A was found in our studies; however, if the cells were disrupted by sonication, rather than N2 cavitation, a fraction of the Rap1A was released from the membrane. Electron microscopy of thin sections of cryofixed, molecular-distillation dried neutrophils labeled with anti-Rap1 antibody alone or double-labeled with anti-Rap1 and anti-cytochrome b peptide antibodies confirmed our biochemical localization, and quantitation showed that more than half of the specific granule-associated Rap1A was translocated to the plasma membrane in PMA-stimulated cells. Ultrastructural analysis of neutrophils phagocytosing Staphylococcus aureus also demonstrated the translocation of Rap1A with cytochrome b. Approximately 70% of the total Rap1A labeling was associated with the phagolysosomal membrane, the site of assembly of the superoxide-generating system. The colocalization and cotranslocation of Rap1A with cytochrome b in resting and activated neutrophils is consistent with a functional association of these two molecules in the intact cell and provides further evidence for a role of this LMWG in the structure or function of the neutrophil superoxide-generating system.

Biological Transport↗

PubMed1989

A membrane-cytoskeletal complex containing Na+,K+-ATPase, ankyrin, and fodrin in Madin-Darby canine kidney (MDCK) cells: implications for the biogenesis of epithelial cell polarity.

In polarized Madin-Darby canine kidney (MDCK) epithelial cells, ankyrin, and the alpha- and beta-subunits of fodrin are components of the basolateral membrane-cytoskeleton and are colocalized with the Na+,K+-ATPase, a marker protein of the basolateral plasma membrane. Recently, we showed with purified proteins that the Na+,K+-ATPase is competent to bind ankyrin with high affinity and specificity (Nelson, W. J., and P. J. Veshnock. 1987. Nature (Lond.). 328:533-536). In the present study we have sought biochemical evidence for interactions between these proteins in MDCK cells. Proteins were solubilized from MDCK cells with an isotonic buffer containing Triton X-100 and fractionated rapidly in sucrose density gradients. Complexes of cosedimenting proteins were detected by analysis of sucrose gradient fractions in nondenaturing polyacrylamide gels. The results showed that ankyrin and fodrin cosedimented in sucrose gradient. Analysis of the proteins from the sucrose gradient in nondenaturing polyacrylamide gels revealed two distinct ankyrin:fodrin complexes that differed in their relative electrophoretic mobilities; both complexes had electrophoretic mobilities slower than that of purified spectrin heterotetramers. Parallel analysis of the distribution of solubilized Na+,K+-ATPase in sucrose gradients showed that there was a significant overlap with the distribution of ankyrin and fodrin. Analysis by nondenaturing polyacrylamide gel electrophoresis showed that the alpha- and beta-subunits of the Na+,K+-ATPase colocalized with the slower migrating of the two ankyrin:fodrin complexes. The faster migrating ankyrin:fodrin complex did not contain Na+,K+-ATPase. These results indicate strongly that the Na+,K+-ATPase, ankyrin, and fodrin are coextracted from whole MDCK cells as a protein complex. We suggest that the solubilized complex containing these proteins reflects the interaction of the Na+,K+-ATPase, ankyrin, and fodrin in the cell. This interaction may play an important role in the spatial organization of the Na+,K+-ATPase to the basolateral plasma membrane in polarized epithelial cells.

Animals↗

PubMed2026

Quantitative trait loci mapping of gene expression and chromatin accessibility in primary fibroblasts reveals shared allelic effects between Latin American and European ancestries.

BACKGROUND: Quantitative Trait Locus (QTL) analysis of molecular data has identified genetic variants associated with traits such as gene expression, and colocalization of these functional QTL with GWAS risk loci has offered insights into the genetic basis of human disease. We employed gene expression (RNA-seq) and chromatin accessibility (ATAC-seq) obtained from human primary fibroblasts to investigate quantitative trait loci (QTLs) in cohorts ascertained for bipolar disorder of European (n = 150) and Latin American (n = 96) ancestries. RESULTS: Leveraging data from three countries of origin (The Netherlands, Colombia, Costa Rica) within our cohort, we characterized differences among individuals at the SNP, gene, and accessible-chromatin levels to compute ancestry-specific expression (e)QTLs and chromatin-accessibility (ca)QTLs. Across ancestries, we observed R2 ≥ 0.93 for eQTL effect sizes and R2 ≥ 0.95 for caQTLs, indicating a high degree of concordance. Integrating chromatin data with expression and genotype information enabled precise fine-mapping of eQTLs, yielding 203 genes with high-confidence (posterior probability > 90%) candidate regulatory pathways. In downstream analyses, transcriptome-wide (TWAS) and chromatin-wide (CWAS) association studies with brain- and skin-related GWAS identified 36 TWAS-significant genes and 77 CWAS-significant open chromatin regions. CONCLUSIONS: These findings underscore the shared genetic regulatory mechanisms across European and Latin American ancestries, while demonstrating that ancestry-specific reference panels enhance the accuracy of TWAS and CWAS in diverse populations. More broadly, this study highlights the value of paired multi-omic datasets from diverse cohorts for interpreting disease-associated genetic variation.

Humans↗