Identification of pleiotropic genes between risk factors of stroke by multivariate metaCCA analysis.
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ABSTRACT:
SUBMITTER: Wang Z
PROVIDER: S-EPMC7394724 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundImmune and skeletal systems physiologically and pathologically interact with each other. Immune and skeletal diseases may share potential pleiotropic genetics factors, but the shared specific genes are largely unknown.ObjectiveThis study aimed to investigate the overlapping genetic factors between multiple diseases (including rheumatoid arthritis (RA), psoriasis, osteoporosis, osteoarthritis, sarcopenia, and fracture).MethodsThe canonical correlation analysis (metaCCA) approach was used to identify the shared genes for six diseases by integrating genome-wide association study (GWAS)-derived summary statistics. The versatile Gene-based Association Study (VEGAS2) method was further applied to refine and validate the putative pleiotropic genes identified by metaCCA.ResultsAbout 157 (p<8.19E-6), 319 (p<3.90E-6), and 77 (p<9.72E-6) potential pleiotropic genes were identified shared by two immune diseases, four skeletal diseases, and all of the six diseases, respectively. The top three significant putative pleiotropic genes shared by both immune and skeletal diseases, including HLA-B, TSBP1, and TSBP1-AS1 (p<E-300), were located in the major histocompatibility complex (MHC) region. Nineteen of 77 putative pleiotropic genes identified by metaCCA analysis were associated with at least one disease in the VEGAS2 analysis. Specifically, the majority (18) of these 19 putative validated pleiotropic genes were associated with RA.ConclusionThe metaCCA method identified some pleiotropic genes shared by the immune and skeletal diseases. These findings help to improve our understanding of the shared genetic mechanisms and signaling pathways underlying immune and skeletal diseases.
| S-EPMC8922324 | biostudies-literature
Project description:BackgroundGenome-wide association studies have been extensively applied in identifying SNP associated with major psychiatric disorders. However, the SNPs identified by the prevailing univariate approach only explain a small percentage of the genetic variance of traits, and the extensive data have shown the major psychiatric disorders have common biological mechanisms and the overlapping pathophysiological pathways.MethodsWe applied the genetic pleiotropy-informed metaCCA method on summary statistics data from the Psychiatric Genomics Consortium Cross-Disorder Group to examine the overlapping genetic relations between the five major psychiatric disorders. Furthermore, to refine all genes, we performed gene-based association analyses for the five disorders respectively using VEGAS2. Gene enrichment analysis was applied to explore the potential functional significance of the identified genes.ResultsAfter metaCCA analysis, 1147 SNPs reached the Bonferroni corrected threshold (p < 1.06 × 10-6) in the univariate SNP-multivariate phenotype analysis, and 246 genes with a significance threshold (p < 3.85 × 10-6) were identified as potentially pleiotropic genes in the multivariate SNP-multivariate phenotype analysis. By screening the results of gene-based p-values, we identified 37 putative pleiotropic genes which achieved significance threshold in metaCCA analyses and were also associated with at least one disorder in the VEGAS2 analyses.LimitationsAlternative approaches and experimental studies may be applied to check whether novel genes could still be identified/substantiated with these methods.ConclusionsThe metaCCA method identified novel variants associated with psychiatric disorders by effectively incorporating information from different GWAS datasets. Our analyses may provide insights for some common therapeutic approaches of these five major psychiatric disorders based on the pleiotropic genes and common mechanisms identified.
| S-EPMC6343670 | biostudies-literature
Project description:Although genome-wide association studies (GWAS) have a dramatic impact on susceptibility locus discovery, this univariate approach has limitations in detecting complex genotype-phenotype correlations. Multivariate analysis is essential to identify shared genetic risk factors acting through common biological mechanisms of autoimmune/autoinflammatory diseases. In this study, GWAS summary statistics, including 41,274 single nucleotide polymorphisms (SNPs) located in 11,516 gene regions, were analyzed to identify shared variants of seven autoimmune/autoinflammatory diseases using the metaCCA method. Gene-based association analysis was used to refine the pleiotropic genes. In addition, GO term enrichment analysis and protein-protein interaction network analysis were applied to explore the potential biological functions of the identified genes. A total of 4,962 SNPs (P < 1.21 × 10-6) and 1,044 pleotropic genes (P < 4.34 × 10-6) were identified by metaCCA analysis. By screening the results of gene-based P-values, we identified the existence of 27 confirmed pleiotropic genes and highlighted 40 novel pleiotropic genes that achieved statistical significance in the metaCCA analysis and were also associated with at least one autoimmune/autoinflammatory in the VEGAS2 analysis. Using the metaCCA method, we identified novel variants associated with complex diseases incorporating different GWAS datasets. Our analysis may provide insights for the development of common therapeutic approaches for autoimmune/autoinflammatory diseases based on the pleiotropic genes and common mechanisms identified.
| S-EPMC7008725 | biostudies-literature
Project description:A dominant approach to genetic association studies is to perform univariate tests between genotype-phenotype pairs. However, analyzing related traits together increases statistical power, and certain complex associations become detectable only when several variants are tested jointly. Currently, modest sample sizes of individual cohorts, and restricted availability of individual-level genotype-phenotype data across the cohorts limit conducting multivariate tests.We introduce metaCCA, a computational framework for summary statistics-based analysis of a single or multiple studies that allows multivariate representation of both genotype and phenotype. It extends the statistical technique of canonical correlation analysis to the setting where original individual-level records are not available, and employs a covariance shrinkage algorithm to achieve robustness.Multivariate meta-analysis of two Finnish studies of nuclear magnetic resonance metabolomics by metaCCA, using standard univariate output from the program SNPTEST, shows an excellent agreement with the pooled individual-level analysis of original data. Motivated by strong multivariate signals in the lipid genes tested, we envision that multivariate association testing using metaCCA has a great potential to provide novel insights from already published summary statistics from high-throughput phenotyping technologies.Code is available at https://github.com/aalto-ics-kepacoanna.cichonska@helsinki.fi or matti.pirinen@helsinki.fiSupplementary data are available at Bioinformatics online.
| S-EPMC4920109 | biostudies-literature
Project description:BackgroundPrevious studies have shown that heart failure (HF) and chronic kidney disease (CKD) have common genetic mechanisms, overlapping pathophysiological pathways, and therapeutic drug-sodium-glucose cotransporter 2 (SGLT2) inhibitors.MethodsThe genetic pleiotropy metaCCA method was applied on summary statistics data from two independent meta-analyses of GWAS comprising more than 1 million people to identify shared variants and pleiotropic effects between HF and CKD. Targets of SGLT2 inhibitors were predicted by SwissTargetPrediction and DrugBank databases. To refine all genes, we performed using versatile gene-based association study 2 (VEGAS2) and transcriptome-wide association studies (TWAS) for HF and CKD, respectively. Gene enrichment and KEGG pathway analyses were used to explore the potential functional significance of the identified genes and targets.ResultsAfter metaCCA analysis, 4,624 SNPs and 1,745 genes were identified to be potentially pleiotropic in the univariate and multivariate SNP-multivariate phenotype analyses, respectively. 21 common genes were detected in both metaCCA and SGLT2 inhibitors' target prediction. In addition, 169 putative pleiotropic genes were identified, which met the significance threshold both in metaCCA analysis and in the VEGAS2 or TWAS analysis for at least one disease.ConclusionWe identified novel variants associated with HF and CKD using effectively incorporating information from different GWAS datasets. Our analysis may provide new insights into HF and CKD therapeutic approaches based on the pleiotropic genes, common targets, and mechanisms by integrating the metaCCA method, TWAS and VEGAS2 analyses, and target prediction of SGLT2 inhibitors.
| S-EPMC8443964 | biostudies-literature
Project description:Observational studies have shown that several risk factors are associated with cardioembolic stroke. However, whether such associations reflect causality remains unknown. We aimed to determine whether established and provisional cardioembolic risk factors are causally associated with cardioembolic stroke. Genetic instruments for atrial fibrillation (AF), myocardial infarction (MI), electrocardiogram (ECG) indices and N-terminal pro-brain natriuretic peptide (NT-pro BNP) were obtained from large genetic consortiums. Summarized data of ischemic stroke and its subtypes were extracted from the MEGASTROKE consortium. Causal estimates were calculated by applying inverse-variance weighted analysis, weighted median analysis, simple median analysis and Mendelian randomization (MR)-Egger regression. Genetically predicted AF was significantly associated with higher odds of ischemic stroke (odds ratio (OR): 1.20, 95% confidence intervals (CI): 1.16-1.24, P = 6.53 × 10-30) and cardioembolic stroke (OR: 1.95, 95% CI: 1.85-2.06, P = 8.81 × 10-125). Suggestive associations were found between genetically determined resting heart rate and higher odds of ischemic stroke (OR: 1.01, 95% CI: 1.00-1.02, P = 0.005), large-artery atherosclerotic stroke (OR: 1.02, 95% CI: 1.00-1.04, P = 0.026) and cardioembolic stroke (OR: 1.02, 95% CI: 1.00-1.04, P = 0.028). There was no causal association of P-wave terminal force in the precordial lead V1 (PTFVI), P-wave duration (PWD), NT-pro BNP or PR interval with ischemic stroke or any subtype.
| S-EPMC8285403 | biostudies-literature
Project description:BackgroundCurrent Genome-Wide Association Studies (GWAS) are performed in a single trait framework without considering genetic correlations between important disease traits. Hence, the GWAS have limitations in discovering genetic risk factors affecting pleiotropic effects.ResultsThis work reports a novel data mining approach to discover patterns of multiple phenotypic associations over 52 anthropometric and biochemical traits in KARE and a new analytical scheme for GWAS of multivariate phenotypes defined by the discovered patterns. This methodology applied to the GWAS for multivariate phenotype highLDLhighTG derived from the predicted patterns of the phenotypic associations. The patterns of the phenotypic associations were informative to draw relations between plasma lipid levels with bone mineral density and a cluster of common traits (Obesity, hypertension, insulin resistance) related to Metabolic Syndrome (MS). A total of 15 SNPs in six genes (PAK7, C20orf103, NRIP1, BCL2, TRPM3, and NAV1) were identified for significant associations with highLDLhighTG. Noteworthy findings were that the significant associations included a mis-sense mutation (PAK7:R335P), a frame shift mutation (C20orf103) and SNPs in splicing sites (TRPM3).ConclusionsThe six genes corresponded to rat and mouse quantitative trait loci (QTLs) that had shown associations with the common traits such as the well characterized MS and even tumor susceptibility. Our findings suggest that the six genes may play important roles in the pleiotropic effects on lipid metabolism and the MS, which increase the risk of Type 2 Diabetes and cardiovascular disease. The use of the multivariate phenotypes can be advantageous in identifying genetic risk factors, accounting for the pleiotropic effects when the multivariate phenotypes have a common etiological pathway.
| S-EPMC3287479 | biostudies-literature
Project description:Atrial fibrillation (AF) increases the risk of ischemic stroke and systemic arterial embolism. However, the risk factors or predictors of stroke in AF patients have not been clarified. Therefore, it is necessary to find effective diagnostic and therapeutic targets. Two datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differently expressed genes (DEGs) were identified between samples of atrial fibrillation without stroke and atrial fibrillation with stroke. Enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) by Gene Set Enrichment Analysis (GSEA), construction and analysis of protein-protein interaction (PPI) network and significant module, and the receiver operator characteristic (ROC) curve analysis were performed. A total of 524 DEGs were common to both datasets. Analysis of KEGG pathways indicated that the top canonical pathways associated with DEGs were ubiquitin-mediated proteolysis, endocytosis, spliceosome, and so on. Ten hub genes (SMURF2, CDC42, UBE3A, RBBP6, CDC5L, NEDD4L, UBE2D2, UBE2B, UBE2I, and MAPK1) were identified from the PPI network and were significantly associated with a diagnosis of atrial fibrillation and stroke (AFST). In summary, a total of 524 DEGs and 10 hub genes were identified between samples of atrial fibrillation without stroke and atrial fibrillation with stroke. These genes may serve as the target of early diagnosis or treatment of AF complicated by stroke.
| S-EPMC7105800 | biostudies-literature
Project description:BackgroundHeroin dependence is a debilitating psychiatric disorder with complex inheritance. Since the dopaminergic system has a key role in rewarding mechanism of the brain, which is directly or indirectly targeted by most drugs of abuse, we focus on the effects and interactions among dopaminergic gene variants.ObjectiveTo study the potential association between allelic variants of dopamine D2 receptor (DRD2), ANKK1 (ankyrin repeat and kinase domain containing 1), dopamine D4 receptor (DRD4), catechol-O-methyl transferase (COMT) and dopamine transporter (SLC6A3) genes and heroin dependence in Hungarian patients.Methods303 heroin dependent subjects and 555 healthy controls were genotyped for 7 single nucleotide polymorphisms (SNPs) rs4680 of the COMT gene; rs1079597 and rs1800498 of the DRD2 gene; rs1800497 of the ANKK1 gene; rs1800955, rs936462 and rs747302 of the DRD4 gene. Four variable number of tandem repeats (VNTRs) were also genotyped: 120 bp duplication and 48 bp VNTR in exon 3 of DRD4 and 40 bp VNTR and intron 8 VNTR of SLC6A3. We also perform a multivariate analysis of associations using Bayesian networks in Bayesian multilevel analysis (BN-BMLA).Findings and conclusionsIn single marker analysis the TaqIA (rs1800497) and TaqIB (rs1079597) variants were associated with heroin dependence. Moreover, -521 C/T SNP (rs1800955) of the DRD4 gene showed nominal association with a possible protective effect of the C allele. After applying the Bonferroni correction TaqIB was still significant suggesting that the minor (A) allele of the TaqIB SNP is a risk component in the genetic background of heroin dependence. The findings of the additional multiple marker analysis are consistent with the results of the single marker analysis, but this method was able to reveal an indirect effect of a promoter polymorphism (rs936462) of the DRD4 gene and this effect is mediated through the -521 C/T (rs1800955) polymorphism in the promoter.
| S-EPMC3696122 | biostudies-literature
Project description:We propose a multivariate genome-wide association test for mixed continuous, binary, and ordinal phenotypes. A latent response model is used to estimate the correlation between phenotypes with different measurement scales so that the empirical distribution of the Fisher's combination statistic under the null hypothesis is estimated efficiently. The simulation study shows that our proposed correlation estimation methods have high levels of accuracy. More importantly, our approach conservatively estimates the variance of the test statistic so that the type I error rate is controlled. The simulation also shows that the proposed test maintains the power at the level very close to that of the ideal analysis based on known latent phenotypes while controlling the type I error. In contrast, conventional approaches-dichotomizing all observed phenotypes or treating them as continuous variables-could either reduce the power or employ a linear regression model unfit for the data. Furthermore, the statistical analysis on the database of the Study of Addiction: Genetics and Environment (SAGE) demonstrates that conducting a multivariate test on multiple phenotypes can increase the power of identifying markers that may not be, otherwise, chosen using marginal tests. The proposed method also offers a new approach to analyzing the Fagerström Test for Nicotine Dependence as multivariate phenotypes in genome-wide association studies.
| S-EPMC5231271 | biostudies-literature