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PubMed2006

Functional annotation of proteins identified in human brain during the HUPO Brain Proteome Project pilot study.

The HUPO Brain Proteome Project is an initiative coordinating proteomics studies to characterise human and mouse brain proteomes. Proteins identified in human brain samples during the project's pilot phase were put into biological context through integration with various annotation sources followed by a bioinformatics analysis. The data set was related to the genome sequence via the genes encoding identified proteins including an assessment of splice variant identification as well as an analysis of tissue specificity of the respective transcripts. Proteins were furthermore categorised according to subcellular localisation, molecular function and biological process, grouped into protein families and mapped to biological pathways they are known to act in. Involvement in pathological conditions was examined based on association with entries in the online version of Mendelian Inheritance in Man and an interaction network was derived from curated protein-proteininteraction data. Overall a non-redundant set of 1804 proteins was identified in human brain samples. In the majority of cases splice variants could be unambiguously identified by unique peptides, including matches to several hypothetical transcripts of known as well as predicted genes.

Alternative Splicing↗

PubMed2004

Ubiquitin interactions of NZF zinc fingers.

Ubiquitin (Ub) functions in many different biological pathways, where it typically interacts with proteins that contain modular Ub recognition domains. One such recognition domain is the Npl4 zinc finger (NZF), a compact zinc-binding module found in many proteins that function in Ub-dependent processes. We now report the solution structure of the NZF domain from Npl4 in complex with Ub. The structure reveals that three key NZF residues (13TF14/M25) surrounding the zinc coordination site bind the hydrophobic 'Ile44' surface of Ub. Mutations in the 13TF14/M25 motif inhibit Ub binding, and naturally occurring NZF domains that lack the motif do not bind Ub. However, substitution of the 13TF14/M25 motif into the nonbinding NZF domain from RanBP2 creates Ub-binding activity, demonstrating the versatility of the NZF scaffold. Finally, NZF mutations that inhibit Ub binding by the NZF domain of Vps36/ESCRT-II also inhibit sorting of ubiquitylated proteins into the yeast vacuole. Thus, the NZF is a versatile protein recognition domain that is used to bind ubiquitylated proteins during vacuolar protein sorting, and probably many other biological processes.

Amino Acid Sequence↗

PubMed2003

Tumor necrosis factor alpha activation of the apoptotic cascade in murine articular chondrocytes is associated with the induction of metalloproteinases and specific pro-resorptive factors.

OBJECTIVE: Tumor necrosis factor alpha (TNFalpha) blockade provides substantive reduction of the symptoms of rheumatoid arthritis (RA). While the biologic actions of TNFalpha have been well characterized in immune and synovial cells, which are known to be major contributors to the progression of cartilage destruction in RA, the current studies were designed to assess the direct effects of TNFalpha on chondrocytes. METHODS: We examined the expression of several groupings of messenger RNA (mRNA) that define key biologic pathways that have previously been associated with either the general actions of TNFalpha or cartilage destruction, in murine articular chondrocytes isolated from wild-type mice and TNFalpha receptor-null (p55/p75(-/-)) mice. RESULTS: TNFalpha induced the expression of multiple mRNA that facilitate apoptosis and lead to apoptosis-induced cell death. The induction of apoptosis was accompanied by the increased expression of several factors involved in the regulation of skeletal tissue proteolysis and resorption. Quantitative increases from 2-fold to >10-fold were seen for inducible nitric oxide synthase, matrix metalloproteinase 3, macrophage colony-stimulating factor, and osteoprotegerin mRNA expression. The dependence of the induction of these mRNA on TNFalpha was confirmed by comparison with the effects of TNFalpha on chondrocytes isolated from receptor-null mice. CONCLUSION: These findings demonstrate that TNFalpha alters the expression of a complex array of genes within murine chondrocytes that contribute to the destruction of joint surfaces, independent of its actions on synovial and immune cells. Further studies are needed to clarify the biologic actions of TNFalpha in human cartilage cells.

Animals↗

PubMed2003

Diverse role of LDL receptor-related protein in the clearance of proteases and in signaling.

The low density lipoprotein receptor-related protein (LRP) is a large endocytic receptor that participates in several biological pathways and plays prominent roles in lipoprotein metabolism and in the catabolism of proteinases involved in coagulation and fibrinolysis. LRP also mediates the cellular entry of certain viruses and toxins and facilitates the activation of various lysosomal enzymes. Deletion of the LRP gene in mice is lethal, confirming an important role for this receptor in development, although its exact function in development is still not known. In addition to its role in the endocytosis of numerous ligands, recent studies are emerging that describe a signaling role for this receptor as well.

Animals↗

PubMed1999

Evolutionary psychology and health: confronting an evolving paradigm.

In much the same way that developments in genetics have opened up new areas of activity in health services, the 'new genetics' has also stimulated a renewal in approaches that try to explain the nature of health behaviours within the context of human biological development. Evolutionary psychology, as an umbrella term for these views, stresses the importance of the brain as an intermediary between genes and individual behaviour. From such a perspective, social context is less important than an understanding of why certain behaviours are 'chosen' by the evolutionary process and how they are predicated on reproductive success. Health policy is a key area where these ideas are likely to become important given evolutionary psychology's focus on the interplay between physiological and psychological factors in determining health behaviours. Health research provides a fertile environment because it is already seeking the hidden biological pathways connecting social status with specific diseases. The challenge represented by evolutionary psychology needs to be taken seriously because of the way in which such ideas mesh with the individualistic basis of much health promotion and health policy. In particular, it poses a challenge when it purports to explain how inequalities in health are not necessarily the result of the unequal distribution of income in society but are natural phenomena. It is also important to engage with such ideas because they increasingly seem likely to occupy the empty ideological space created by the disappearance of politics in policy and as such may have a greater impact than would otherwise be the case.

Biological Evolution↗

PubMed2005

Prediction of functional modules based on gene distributions in microbial genomes.

We present a computational method for prediction of functional modules that can be directly applied to the newly sequenced microbial genomes for predicting gene functions and the component genes of biological pathways. We first quantify the functional relatedness among genes based on their distribution (i.e., their existences and orders) across multiple microbial genomes, and obtain a gene network in which every pair of genes is associated with a score representing their functional relatedness. We then apply a threshold-based clustering algorithm to this gene network, and obtain modules for each of which the number of genes is bounded from above by a pre-specified value and the component genes are more strongly functionally related to each other than genes across the predicted modules. Particularly, when the module size is bounded by 130, we obtain 167 functional modules covering 813 genes for Escherichia coli K12, and 138 functional modules covering 731 genes for Bacillus subtilis subsp. subtilis str. 168. We have used the gene ontology (GO) information to assess the prediction results. The GO similarities among the genes of the same functional module are compared with the GO similarities among the genes that are randomly clustered together. This comparison reveals that our predicted functional modules are statistically and biologically significant, and the genes of the same functional module share more commonality in terms of biological process than in terms of molecular function or cellular component. We have also examined the predicted functional modules that are common to both Escherichia coli K12 and Bacillus subtilis subsp. subtilis str. 168, and provide explanations for some functional modules.

Cluster Analysis↗

PubMed2026

A genome-wide investigation of depression among individuals with and without irritability.

Individuals presenting with both depression and irritability may constitute a different group of individuals with respect to those presenting without irritability, but their biological differences remain unknown. We aimed to identify genetic variants associated with depression among individuals with and without irritability, highlight biological pathways, and test for genetic associations with other traits. We conducted a genome-wide association study (GWAS) using data from the UK Biobank (N = 487,409). We identified a group of individuals presenting with depression and reporting never having experienced irritability (depression without irritability, n = 35,857, 11.8%), and another with depression and reporting having experienced irritability (depression with irritability, n = 23,613, 8.1%) and compared them to controls with no depression or irritability (n = 268,012). The GWAS of depression without irritability identified 2 SNPs which reached genome-wide significance (P < 5×10-8; rs72795440 and rs1233494). The GWAS of depression with irritability (NGWAS = 292,485) identified 3 SNPs reaching genome-wide significance (rs2815748, rs102275, and rs7227069). When comparing SNPs between depression phenotypes, 15 SNPs had significantly different effect sizes. Patterns of genetic correlation with 44 complex traits were overall similar between the 2 depression phenotypes, with the highest genetic overlap observed with anxiety for depression without irritability (rg = .77) and neuroticism for depression with irritability (rg = .76). This study shed light into common and distinct biological factors characterizing depression among individuals with and without irritability and contribute to better understanding the genetic architecture of depression to potentially inform treatment and personalized medicine.

Humans↗

PubMed2005

Identification of global gene expression differences between human lens epithelial and cortical fiber cells reveals specific genes and their associated pathways important for specialized lens cell functions.

PURPOSE: In order to identify specific genes that may play important roles in maintaining the specialized functions of lens epithelial and fiber cells, we have analyzed the global gene expression profiles of these two cell types in the human lens. This analysis will also reveal those genes that are exclusively expressed in the epithelial and cortical fiber cells and those genes that may play important roles in the differentiation of epithelial cells to mature fiber cells. METHODS: Oligonucleotide microarray hybridization was used to analyze the expression profiles of 22,215 genes between adult (average age greater than 56 years) human lens epithelial and cortical fiber cells. The expression levels of selected genes were further compared by semi-quantitative RT-PCR and selected genes were functionally clustered into common categories using the EASE bioinformatics software package. RESULTS: Analysis of three separate microarray hybridizations revealed 1,196 transcripts that exhibit increased expression and 1,278 transcripts that exhibit decreased expression at the 2 fold or greater level between lens epithelial cells and cortical fiber cells on all three of the arrays analyzed. Of these, 222 transcripts exhibited increased expression and 135 transcripts exhibited decreased expression by an average of 5 fold or greater levels on all three arrays. Semi-quantitative RT-PCR analysis of 21 randomly selected genes revealed identical expression patterns as those detected by microarray hybridization indicating that the microarray data are accurate. Functional clustering of the identified gene expression patterns using the EASE program revealed a wide variety of biological pathways that exhibited altered expression patterns between the two cell types including mRNA processing, cell adhesion, cell proliferation, translation, protein folding, oxidative phosphorylation, and apoptosis, among others. CONCLUSIONS: These data reveal novel and previously identified gene expression differences between lens epithelial and cortical fiber cells. The gene expression differences indicate distinct pathways and functions important for the specialization of lens epithelial and fiber cells and provide insight into potential mechanisms important for lens cell differentiation.

Aged↗

PubMed2004

Posttraumatic stress disorder and physical illness: results from clinical and epidemiologic studies.

Research indicates that exposure to traumatic stressors and psychological trauma is widespread. The association of such exposures with posttraumatic stress disorder (PTSD) and other mental health conditions is well known. However, epidemiologic research increasingly suggests that exposure to these events is related to increased health care utilization, adverse health outcomes, the onset of specific diseases, and premature death. To date, studies have linked traumatic stress exposures and PTSD to such conditions as cardiovascular disease, diabetes, gastrointestinal disease, fibromyalgia, chronic fatigue syndrome, musculoskeletal disorders, and other diseases. Evidence linking cardiovascular disease and exposure to psychological trauma is particularly strong and has been found consistently across different populations and stressor events. In addition, clinical studies have suggested the biological pathways through which stressor-induced diseases may be pathologically expressed. In particular, recent studies have implicated the hypothalamic-pituitary-adrenal (HPA) and the sympathetic-adrenal-medullary (SAM) stress axes as key in this pathogenic process, although genetic and behavioral/psychological risk factors cannot be ruled out. Recent findings, indicating that victims of PTSD have higher circulating T-cell lymphocytes and lower cortisol levels, are intriguing and suggest that chronic sufferers of PTSD may be at risk for autoimmune diseases. To test this hypothesis, we assessed the association between chronic PTSD in a national sample of 2,490 Vietnam veterans and the prevalence of common autoimmune diseases, including rheumatoid arthritis, psoriasis, insulin-dependent diabetes, and thyroid disease. Our analyses suggest that chronic PTSD, particularly comorbid PTSD or complex PTSD, is associated with all of these conditions. In addition, veterans with comorbid PTSD were more likely to have clinically higher T-cell counts, hyperreactive immune responses on standardized delayed cutaneous hypersensitivity tests, clinically higher immunoglobulin-M levels, and clinically lower dehydroepiandrosterone levels. The latter clinical evidence confirms the presence of biological markers consistent with a broad range of inflammatory disorders, including both cardiovascular and autoimmune diseases.

Arthritis, Rheumatoid↗

PubMed2006

Impact of genetic variants in IL-4, IL-4 RA and IL-13 on the anti-pneumococcal antibody response.

BACKGROUND: Significant differences in immune responses upon vaccination have been described, suggesting genetics are important in determining the magnitude of vaccine responses. The interleukin (IL)-4 pathway, including IL-4, IL-13 and the IL-4 receptor alpha chain (IL-4 Ralpha), is central to humoral responses and therefore could have an impact on vaccine responsiveness. OBJECTIVE: To investigate whether single nucleotide polymorphisms (SNPs) in the IL-4, IL-13 and IL-4 RA genes influence pneumococcal serotype-specific IgG antibody responses. METHODS: SNPs in the IL-4 gene (C -589T, G2979T), the IL-13 gene (G -1112A, Arg130Gln) and in the IL-4 RA gene (Ile50Val, Gln551Arg) were investigated in isolation and in combination, for their influence on serotype-specific IgG antibody responses upon combined pneumococcal conjugate and polysaccharide vaccinations in children with a history of recurrent otitis media. RESULTS: Lower antibody responses were observed for alleles previously associated with atopy, IL-4 -589T, IL-4 2979T and IL-4 Ralpha 551Gln. Effects were stronger in gene haplotype combinations or in multiple haplotype combination analyses. CONCLUSION: This study highlights the importance of host genetic factors in vaccine responses. Furthermore, it supports the approach of studying the effect of combinations of multiple alleles, in haplotypes or in combinations of haplotypes, on complex phenotypes within a biological pathway.

Antibodies, Bacterial↗

PubMedDate not supplied

DNA microarrays in pediatric cancer.

Childhood cancer, like all cancer, is at heart a genetic disease. Consequently, fundamental understanding of the oncogenic process is likely to be beneficially addressed by genetic methodology. Current methods have largely focused on single-gene defects, like chimeric genes, which are present in many sarcomas and leukemias. Real understanding is more likely to derive from a genome-wide analysis of these malignancies. Recent technologic advances have made it possible to simultaneously assess the entire expressed gene profile, or transcriptome, of a given cancer. Foremost among these methods is gene expression profiling using DNA microarrays. Two basic approaches predominate: spotted arrays and photolithography arrays. Regardless of the method, the resulting information can be used to create disease profiles, but only if appropriate bioinformatic solutions are employed. Common analytic approaches include two-way expression comparisons, or scatter analyses; outlier gene analysis, to identify significantly dysregulated genes; dendrogram analyses, as pioneered by Eisen; cluster analyses to identify diagnostic or biologic groups; and various forms of functional analyses to identify relevant genes and biologic pathways. Studies of both adult and pediatric cancer have demonstrated the feasibility of such analyses to identify both diagnostic and prognostic groups of tumors. Acute childhood leukemias have been grouped into myelogenous and lymphoid, and even B- and T-cell subsets. Breast cancer prognostic groups have been identified on the basis of a small subset of expressed genes. In addition, preliminary data on childhood sarcomas appear to identify both diagnostic and prognostic subsets. Specifically, embryonal rhabdomyosarcoma could be distinguished from alveolar rhabdomyosarcoma, and even morphologically mixed embryonal and alveolar rhabdomyosarcoma showed similar gene expression profiles in both histologies. Further, collaborative studies using clustering analyses appear to identify prognostic groups of diverse sarcomas. Larger institutional and cooperative group studies are currently underway to validate these preliminary findings.

Animals↗

PubMed2026

Early-adulthood body mass index, mammographic density and post-menopausal breast cancer risk: a mediation analysis.

BACKGROUND: To explore potential mechanistic pathways and inform prevention strategies, this study examined whether mammographic density (MD) mediates the inverse association between higher early-adulthood body mass index (BMI) and lower post-menopausal breast cancer risk. METHODS: We analysed data from 33,816 post-menopausal women in the UK PROCAS cohort, with self-reported BMI at age 20. MD was measured using full-field digital mammography and assessed using the visual analogue scale (VAS) percentage density and Volpara®-derived fibroglandular volume (FGV). Counterfactual mediation modelling estimated natural direct and indirect effects. RESULTS: Over a median follow-up of 10.44 years, there were 1261 new post-menopausal breast cancers. Higher VAS and FGV were associated with increased breast cancer risk. BMI at age 20 was associated with lower VAS density and reduced breast cancer risk [Hazard Ratio per 5 kg/m²: 0.849 (0.771-0.938)]. The calculated proportion mediated by VAS density was 59.9% (32.6-150), after accounting for intermediate confounding by BMI in later adulthood. FGV was positively associated with higher BMI at cohort entry but not at age 20. CONCLUSIONS: Lower VAS density may partially explain the inverse association between early-adulthood BMI and post-menopausal breast cancer risk. The link between FGV and breast cancer risk may represent a different biological pathway.

Journal Article↗

PubMed2002

Phenotypic consequences of mutations in the conserved motifs of the putative helicase domain of the human Cockayne syndrome group B gene.

Cockayne syndrome (CS) is a human genetic disorder characterized by several neurological and developmental abnormalities. Two genetic complementation groups, CS-A and CS-B, have been identified. The CSB protein belongs to helicase superfamily 2, and to the SWI/SNF family of proteins. The CSB protein is implicated in transcription-coupled repair (TCR), basal transcription and chromatin remodeling. In addition, CS cells undergo UV-induced apoptosis at much lower doses than normal cells. However, the molecular function of the CSB protein in these biological pathways has remained unclear. Evidence indicates that the integrity of the Walker A and B boxes (motifs I and II) are important for CSB function, but the functional significance of the helicase motifs Ia, III--IV has not been previously examined. In this study, single amino acid changes in highly conserved residues of helicase motifs Ia, III, V, VI and a second putative nucleotide-binding motif (NTB) of the CSB protein were generated by site-directed mutagenesis to analyze the genetic function of the CSB protein in survival, RNA synthesis recovery and apoptosis after UV treatment. The survival analysis of these CS-B mutant cell lines was also performed after treatment with the chemical carcinogen, 4-nitroquinoline-1-oxide (4-NQO). The lesions induced by UV light, cyclobutane pyrimidine dimers, are known to be repaired by TCR whereas the lesions induced by 4-NQO are repaired by global genome repair. The results of this study demonstrate that the point mutations in highly conserved residues of helicase motifs Ia, III, V and VI abolished the genetic function of the CSB protein in survival, RNA synthesis recovery and apoptosis after UV treatment. Similarly, the same mutants failed to complement the sensitivity toward 4-NQO. Thus, the integrity of these helicase motifs is important for the biological function of the CSB protein. On the contrary, a point mutation in a C-terminal, second, NTB motif of the CSB protein showed full complementation in the ability to repair damage induced by UV light or 4-NQO, suggesting that this motif is not important for the CSB repair function.

4-Nitroquinoline-1-oxide↗

PubMed1991

The translocation of inhaled silicon dioxide: an empirically derived compartmental model.

The movement of inhaled silicon dioxide particles was studied by measuring the amounts in alveolar fluid and cells, lung tissue, and lymphoid tissue during the 6 months following short-term aerosol exposure of Fischer 344 rats. A variety of first-order compartmental models were fit to data from nine exposure experiments to identify the most feasible biologic pathways for the transfer of material among these sites and out of the body. A multivariate least-squares approach was used to simultaneously fit the data from several compartments. The results indicate that transfer between alveolar cells and lung tissue occurs in both directions, suggesting that silica can reenter the alveolar space from the lung tissue. This feature has not been included in previously published models. The results also indicate that transfer from lung tissue to the mediastinal lymph nodes and thymus is indirect; there are one or more unidentified extrapulmonary compartments that receive silica from the lung. Rates of transfer among compartments were dependent on mineral type (quartz or cristobalite), heat treatment, and exposure dose. There was no evidence for direct clearance from the alveolar space via the tracheobronchial tract.

Animals↗

PubMed2005

RNA interference in neuroscience: progress and challenges.

1.RNA interference (RNAi) is a recently discovered biological pathway that mediates post-transcriptional gene silencing. The process of RNAi is orchestrated by an increasingly well-understood cellular machinery. 2. The common entry point for both natural and engineered RNAi are double stranded RNA molecules known as short interfering RNAs (siRNAs), that mediate the sequence-specific identification and degradation of the targeted messenger RNA (mRNA). The study and manipulation of these siRNAs has recently revolutionized biomedical research. 3. In this review, we first provide a brief overview of the process of RNAi, focusing on its potential role in brain function and involvement in neurological disease. We then describe the methods developed to manipulate RNAi in the laboratory and its applications to neuroscience. Finally, we focus on the potential therapeutic application of RNAi to neurological disease.

Animals↗

PubMed2002

Identification of a potent and selective pharmacophore for Cdc25 dual specificity phosphatase inhibitors.

Small molecules provide powerful tools to interrogate biological pathways but many important pathway participants remain refractory to inhibitors. For example, Cdc25 dual-specificity phosphatases regulate mammalian cell cycle progression and are implicated in oncogenesis, but potent and selective inhibitors are lacking for this enzyme class. Thus, we evaluated 10,070 compounds in a publicly available chemical repository of the National Cancer Institute for in vitro inhibitory activity against oncogenic, full-length, recombinant human Cdc25B. Twenty-one compounds had mean inhibitory concentrations of <1 microM; >75% were quinones and >40% were of the para-naphthoquinone structural type. Most notable was NSC 95397 (2,3-bis-[2-hydroxyethylsulfanyl]-[1,4]naphthoquinone), which displayed mixed inhibition kinetics with in vitro K(i) values for Cdc25A, -B, and -C of 32, 96, and 40 nM, respectively. NSC 95397 was more potent than any inhibitor of dual specificity phosphatases described previously and 125- to 180-fold more selective for Cdc25A than VH1-related dual-specificity phosphatase or protein tyrosine phosphatase 1b, respectively. Modification of the bis-thioethanol moiety markedly decreased enzyme inhibitory activity, indicating its importance for bioactivity. NSC 95397 showed significant growth inhibition against human and murine carcinoma cells and blocked G(2)/M phase transition. A potential Cdc25 site of interaction was postulated based on molecular modeling with these quinones. We propose that inhibitors based on this chemical structure could serve as useful tools to probe the biological function of Cdc25.

Amino Acid Motifs↗

PubMed2003

Gene discovery using a human vestibular schwannoma cDNA library constructed from a patient with neurofibromatosis type 2 (NF2).

BACKGROUND: Despite a strong association of schwannomin/merlin gene mutations with vestibular schwannoma formation, the regulatory mechanisms and biologic pathways involved are still largely unknown. The hypothesis of this study is that the genesis and growth characteristics of neurofibromatosis type 2 (NF2)-associated vestibular schwannomas are determined by genetic alterations that vary in gene transcript expression; this transcript expression includes oncogenic gene products that may be identified by construction and sequencing of a cDNA library from NF2-associated vestibular schwannoma. METHODS: Approximately 3 mL of fresh tumor was obtained during resection of a 4-cm vestibular schwannoma from a patient with NF2. Poly(A)(+) mRNA was isolated, synthesized into double-stranded cDNA, and unidirectionally inserted into Uni-Zap XR (Stratagene, La Jolla, CA) bacteriophage vectors. Bacteriophage vectors containing cDNA inserts were processed into phagemids according to Uni-Zap XR protocol, and inserted vectors were sequenced and analyzed using BLAST software (National Institutes of Health, Bethesda, MD) with GenBank, EMBL, DDBJ, and PBD databases. RESULTS: The cDNA library contained 2.4 million primary plaques. Inserts averaged 1.8 kilobases (kb) in length, with a range of 0.8 to 3.0 kb. BLAST multidatabase comparison of the sequence data obtained from 50 randomly selected clones yielded identification of 13 sequences representing known human genes and 17 sequences representing cloned sequences with unknown function. Three clones represented sequences not previously described in vestibular schwannomas but strongly implicated in oncogenesis within other tissues. CONCLUSIONS: These data have implications for understanding the molecular mechanisms of vestibular schwannoma tumor biology. Identified genes may provide future diagnostic/prognostic markers and therapeutic targets.

Adult↗

PubMed2026

Integrative Analysis Uncover the Effects and Multi-Omics Features of Thigh Muscle Fat Infiltration.

The health impacts and underlying biological pathways of thigh muscle fat infiltration (TMFI) remain incompletely understood. In this study, we analyzed TMFI measured by magnetic resonance imaging in 55,120 UK Biobank participants and found that higher TMFI was significantly associated with all-cause mortality as well as with all major system-specific diseases examined (p values ranged from 2.50 × 10-88 to 9.97 × 10-04). TMFI also mediated the effects of lifestyle factors on health-related outcomes, with mediation proportions ranging from 6.7% to 71.7%. A genome-wide association study (GWAS) identified 79 lead single nucleotide polymorphisms (SNPs) linked to TMFI, and the polygenic risk score for TMFI was significantly associated with mortality and all incident diseases across examined organ systems in an independent subset of UK Biobank participants of European ancestry who were not included in the TMFI GWAS (n = 362,286, all p < 0.05). Gene-drug interactions identified multiple drugs that could potentially modulate TMFI. Analysis of single-cell transcriptomic data indicated that myogenic cells were strongly linked to TMFI (p = 7.08 × 10-08). Summary-data-based Mendelian randomization and Transcriptome-Wide Association Study analyses revealed numerous genes whose expression in specific tissues was associated with TMFI. Proteomic and metabolomic profiling uncovered a broad array of circulating biomarkers associated with TMFI, many of which mediated the effects of modifiable factors and genetic risk on TMFI. Overall, our results highlight the biological relevance of TMFI to human health and provide insights into the multi-omics mechanisms underlying TMFI, identifying potential targets for interventions.

Humans↗