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Hierarchical association of COPD to principal genetic components of biological systems.

ABSTRACT: Many disease-causing genetic variants converge on common biological functions and pathways. Precisely how to incorporate pathway knowledge in genetic association studies is not yet clear, however. Previous approaches employ a two-step approach, in which a regular association test is first performed to identify variants associated with the disease phenotype, followed by a test for functional enrichment within the genes implicated by those variants. Here we introduce a concise one-step approach, Hierarchical Genetic Analysis (Higana), which directly computes phenotype associations against each function in the large hierarchy of biological functions documented by the Gene Ontology. Using this approach, we identify risk genes and functions for Chronic Obstructive Pulmonary Disease (COPD), highlighting microtubule transport, muscle adaptation, and nicotine receptor signaling pathways. Microtubule transport has not been previously linked to COPD, as it integrates genetic variants spread over numerous genes. All associations validate strongly in a second COPD cohort.

SUBMITTER: Carlin DE

PROVIDER: S-EPMC10212185 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Hierarchical association of COPD to principal genetic components of biological systems.

Carlin Daniel E DE Larsen Simon J SJ Sirupurapu Vikram V Cho Michael H MH Silverman Edwin K EK Baumbach Jan J Ideker Trey T

PloS one 20230525 5

Many disease-causing genetic variants converge on common biological functions and pathways. Precisely how to incorporate pathway knowledge in genetic association studies is not yet clear, however. Previous approaches employ a two-step approach, in which a regular association test is first performed to identify variants associated with the disease phenotype, followed by a test for functional enrichment within the genes implicated by those variants. Here we introduce a concise one-step approach, H ...[more]

PMID: 37228113

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Project description:BackgroundConcentrated breeding effort to produce various body structures and behaviors of dogs to suit human demand has inadvertently produced unwanted traits and diseases that accompany the morphological and behavioral phenotypes. We explored the relationship between pelvic conformation and canine hip dysplasia (HD) because purebred dogs which are predisposed, or not, to HD share common morphologic features, respectively. Thirteen unique bilateral anatomical features of the pelvis were measured on 392 dogs of 51 breeds and 95 mixed breed dogs. Principal components (PCs) were derived to describe pelvic morphology. Dogs were genotyped at ~183,000 single nucleotide polymorphisms and their hip conformation was measured by the Norberg angle and angle of inclination between the femoral neck and diaphysis.ResultsNo associations reached genome wide significance for the Norberg angle when averaged over both hips. PC1 was negatively correlated with the Norberg angle (r = -0.31; P < 0.05) but not the angle of inclination (r = -0.08; P > 0.05). PC1, 2, 4, and 5 differed significantly between male and female dogs confirming pelvic sexual dimorphism. With sex as a covariate, the eigenvector contribution to PC1 reflected the overall size of the pelvis and was significantly associated with the IGF-1 locus, a known contributor to canine body size. PC3, which represented a tradeoff between ilial length and ischial length in which a longer ischium is associated with a shorter ilium, was significantly associated with a marker on canine chromosome 16:5181388 bp. The closest candidate gene is TPK1, a thiamine-dependent enzyme and part of the PKA complex. Associations with the remaining PCs did not reach genome wide significance.ConclusionIGF-1 was associated with the overall size of the pelvis and sex is related to pelvic size. Ilial/ischial proportion is genetically controlled and the closest candidate gene is thiamine-dependent and affects birth weight and development of the nervous system. Dogs with larger pelves tend to have smaller NAs consistent with increased tendency toward HD in large breed dogs. Based on the current study, pelvic shape alone was not strongly associated with canine hip dysplasia.

Project description:It is known that microglia morphology and function are closely related, but only few studies have objectively described different morphological subtypes. To address this issue, morphological parameters of microglial cells were analyzed in a rat model of aseptic neuroinflammation. After the injection of a single dose of the enzyme neuraminidase (NA) within the lateral ventricle (LV) an acute inflammatory process occurs. Sections from NA-injected animals and sham controls were immunolabeled with the microglial marker IBA1, which highlights ramifications and features of the cell shape. Using images obtained by section scanning, individual microglial cells were sampled from various regions (septofimbrial nucleus, hippocampus and hypothalamus) at different times post-injection (2, 4 and 12 h). Each cell yielded a set of 15 morphological parameters by means of image analysis software. Five initial parameters (including fractal measures) were statistically different in cells from NA-injected rats (most of them IL-1β positive, i.e., M1-state) compared to those from control animals (none of them IL-1β positive, i.e., surveillant state). However, additional multimodal parameters were revealed more suitable for hierarchical cluster analysis (HCA). This method pointed out the classification of microglia population in four clusters. Furthermore, a linear discriminant analysis (LDA) suggested three specific parameters to objectively classify any microglia by a decision tree. In addition, a principal components analysis (PCA) revealed two extra valuable variables that allowed to further classifying microglia in a total of eight sub-clusters or types. The spatio-temporal distribution of these different morphotypes in our rat inflammation model allowed to relate specific morphotypes with microglial activation status and brain location. An objective method for microglia classification based on morphological parameters is proposed. Main points Microglia undergo a quantifiable morphological change upon neuraminidase induced inflammation.Hierarchical cluster and principal components analysis allow morphological classification of microglia.Brain location of microglia is a relevant factor.

Project description:To decipher gene regulatory networks, we used systematic suppression of 97 transcription factors (TFs) and 7 other genes with shRNA in mouse embryonic stem (ES) cells, followed by global gene expression profiling. Meta-analysis of these data together with the earlier data obtained by the induction of 50 TFs and the existing genome-wide data on TF binding sites identified the sets of regulated target genes for 23 TFs. Principal component analysis shows different roles of two groups of TFs that are active in ES cells: Pou5f1 and Sox2 support the expression of their target genes and prevent the upregulation of trophectoderm-related genes, whereas Esrrb, Sall4, Nanog, Gbx2, Grhl2, Mtf2, Aff1, Tcfap4, and Cdc5l support the expression of targets of Esrrb, including glycolysis genes, and prevent upregulation of targets of Trp53 and Polycomb TFs. If TFs from the second group are downregulated while Pou5f1 and Sox2 are still active, then the cell state changes towards epiblast lineages. Sequences for shRNA were designed to target 3 untranslated region of genes (Supplementary Table S8). Gene expression change was checked with real time qPCR (Supplementary Figure S7) and Westerm blot. ES cells (ES[MC1R(20)], passage 20) were cultured without feeders and were co-transfected with 1.6 g of shRNA expression vector and 0.4 g of pPyCAG-EGFP-IP carrying expression cassettes for puromycin resistant genes and EGFP using Effectene (Qiagen). Transfected cells were cultured in presence of 1.5 g/ml of puromycin and were harvested at 72 h after transfection. Mock cells were treated with transfection reagent without DNA and cultured in the absence of puromycin. Experiments were done in 3 replications with 2 of them used for gene expression profiling with microarrays. Total RNA was isolated by TRIzol (Invitrogen) after 2 days. Cy3-CTP labeled sample targets were prepared with total RNA by Low RNA Input Fluorescent Linear Amplification Kit (Agilent). Cy5-CTP labeled reference target was Stratagene Universal Mouse Reference RNA. Note that the processed data in the paper, which is also attached as GSE26520_Table_data.txt.gz, is slightly different from the values columns in each sample. The original processed data are normalized with a batch method, as the new batches of arrays added in the set. The value columns in this submission reflect full normalization as described in the data processing fields in each sample.

Dataset Information

Hierarchical association of COPD to principal genetic components of biological systems.

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Hierarchical association of COPD to principal genetic components of biological systems.

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