Shared Genetic Etiology between Alzheimer's Disease and Blood Levels of Specific Cytokines and Growth Factors.
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ABSTRACT:
SUBMITTER: van der Linden RJ
PROVIDER: S-EPMC8226721 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Epidemiological evidence supports the observation that subjects with type 2 diabetes (T2D) are at higher risk to develop Alzheimer's disease (AD). However, whether and how these two conditions are causally linked is unknown. Possible mechanisms include shared genetic risk factors, which were investigated in this study based on recent genome wide association study (GWAS) findings. In order to achieve our goal, we retrieved single nucleotide polymorphisms (SNPs) associated with T2D and AD from large-scale GWAS meta-analysis consortia and tested for overlap among the T2D- and AD-associated SNPs at various p-value thresholds. We then explored the function of the shared T2D/AD GWAS SNPs by leveraging expressional quantitative trait loci, pathways, gene ontology data, and co-expression networks. We found 927 SNPs associated with both AD and T2D with p-value ≤0.01, an overlap significantly larger than random chance (overlapping p-value of 6.93E-28). Among these, 395 of the shared GWAS SNPs have the same risk allele for AD and T2D, suggesting common pathogenic mechanisms underlying the development of both AD and T2D. Genes influenced by shared T2D/AD SNPs with the same risk allele were first identified using a SNP annotation variation (ANNOVAR) software, followed by using Association Protein-Protein Link Evaluator (DAPPLE) software to identify additional proteins that are known to physically interact with the ANNOVAR gene annotations. We found that gene annotations from ANNOVAR and DAPPLE significantly enriched specific KEGG pathways pertaining to immune responses, cell signaling and neuronal plasticity, cellular processes in which abnormalities are known to contribute to both T2D and AD pathogenesis. Thus, our observation suggests that among T2D subjects with common genetic predispositions (e.g., SNPs with consistent risk alleles for T2D and AD), dysregulation of these pathogenic pathways could contribute to the elevated risks for AD in subjects. Interestingly, we found that 532 of the shared T2D/AD GWAS SNPs had divergent risk alleles in the two diseases. For individual shared T2D/AD SNPs with divergent alleles, one of the allelic forms may contribute to one of the diseases (e.g., T2D), but not necessarily to the other (e.g., AD), or vice versa. Collectively, our GWAS studies tentatively support the epidemiological observation of disease concordance between T2D and AD. Moreover, the studies provide the much needed information for the design of future novel therapeutic approaches, for a subpopulation of T2D subjects with genetic disposition to AD, that could benefit T2D and reduce the risk for subsequent development of AD.
| S-EPMC6021176 | biostudies-literature
Project description:Patients with late-onset Alzheimer's disease (LOAD) frequently manifest comorbid neuropsychiatric symptoms with depression and anxiety being most frequent, and individuals with major depressive disorder (MDD) have an increased prevalence of LOAD. This suggests shared etiologies and intersecting pathways between LOAD and MDD. We performed pleiotropy analyses using LOAD and MDD GWAS data sets from the International Genomics of Alzheimer's Project (IGAP) and the Psychiatric Genomics Consortium (PGC), respectively. We found a moderate enrichment for SNPs associated with LOAD across increasingly stringent levels of significance with the MDD GWAS association (LOAD|MDD), of maximum four and eightfolds, including and excluding the APOE-region, respectively. Association analysis excluding the APOE-region identified numerous SNPs corresponding to 40 genes, 9 of which are known LOAD-risk loci primarily in chromosome 11 regions that contain the SPI1 gene and MS4A genes cluster, and others were novel pleiotropic risk-loci for LOAD conditional with MDD. The most significant associated SNPs on chromosome 11 overlapped with eQTLs found in whole-blood and monocytes, suggesting functional roles in gene regulation. The reverse conditional association analysis (MDD|LOAD) showed a moderate level, ~sevenfold, of polygenic overlap, however, no SNP showed significant association. Pathway analyses replicated previously reported LOAD biological pathways related to immune response and regulation of endocytosis. In conclusion, we provide insights into the overlapping genetic signatures underpinning the common phenotypic manifestations and inter-relationship between LOAD and MDD. This knowledge is crucial to the development of actionable targets for novel therapies to treat depression preceding dementia, in an effort to delay or ultimately prevent the onset of LOAD.
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Project description:IntroductionLate-onset Alzheimer's disease (LOAD) manifests comorbid neuropsychiatric symptoms and posttraumatic stress disorder (PTSD) is associated with an increased risk for dementia in late life, suggesting the two disorders may share genetic etiologies.MethodsWe performed genetic pleiotropy analysis using LOAD and PTSD genome-wide association study (GWAS) datasets from white and African-American populations, followed by functional-genomic analyses.ResultsWe found an enrichment for LOAD across increasingly stringent levels of significance with the PTSD GWAS association (LOAD|PTSD) in the discovery and replication cohorts and a modest enrichment for the reverse conditional association (PTSD|LOAD). LOAD|PTSD association analysis identified and replicated the MS4A genes region. These genes showed similar expression pattern in brain regions affected in LOAD, and across-brain-tissue analysis identified a significant association for MS4A6A. The African-American samples showed moderate enrichment; however, no false discovery rate-significant associations.DiscussionWe demonstrated common genetic signatures for LOAD and PTSD and suggested immune response as a common pathway for these diseases.
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Project description:Although dramatic progress has been achieved in the understanding and treatment of multiple sclerosis (MS) and ischemic stroke (IS), more precise and instructive support is required for further research. Recent large-scale genome-wide association studies (GWASs) have already revealed risk variants for IS and MS, but the common genetic etiology between MS and IS remains an unresolved issue. This research was designed to overlapping genes between MS and IS and unmask their transcriptional features. We designed a three-section analysis process. Firstly, we computed gene-based analyses of MS GWAS and IS GWAS data sets by VGEAS2. Secondly, overlapping genes of significance were identified in a meta-analysis using the Fisher's procedure. Finally, we performed gene expression analyses to confirm transcriptional changes. We identified 24 shared genes with Bonferroni correction (P combined < 2.31E-04), and five (FOXP1, CAMK2G, CLEC2D, LBH, and SLC2A4RG) had significant expression differences in MS and IS gene expression omnibus data sets. These meaningful shared genes between IS and MS shed light on the underlying genetic etiologies shared by the diseases. Our results provide a basis for in-depth genomic studies of associations between MS and IS.
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Project description:Idiopathic achalasia is a disease that is characterized by the absence of peristalsis and incomplete relaxation of the lower esophageal sphincter, which is accompanied by dysphagia, regurgitation, chest pain and weight loss. The role of inflammatory infiltrates in the pathogenesis of achalasia remains controversial, although the infiltrating cell profile in the tissue has been previously characterized histologically and immunohistochemically. The present study aimed to evaluate the serum levels of 27 protein biomarkers to determine their association with achalasia and the clinical disease characteristics. The cytokine, chemokine and growth factor serum profiles of 68 patients with achalasia and 39 healthy individuals were explored using the 27-Bio-Plex Pro Human Cytokine assay. Reductions in the levels of inflammatory mediators IL-1β, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-15, IL-17, fibroblast growth factor, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-γ, monocyte chemoattractant protein-1, macrophage inflammatory protein-1 (MIP-1)α and MIP-1β, regulated upon activation normal T cell expressed and presumably secreted, TNF-α and VEGF were detected in the serum samples of patients with achalasia compared with those in the control group (P<0.05). However, significant associations between the expression in the levels of inflammatory factors and clinical characteristics of the patients were not found (P>0.05). These results suggest that achalasia is a disease that has a local but not a systemic inflammatory pattern. Further studies are required to improve the current understanding of the mechanism underlying this disease.
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Project description:The clinical comorbidity of alcohol dependence (AD) and major depressive disorder (MDD) is well established, whereas genetic factors influencing co-occurrence remain unclear. A recent study using polygenic risk scores (PRS) calculated based on the first-wave Psychiatric Genomics Consortium MDD meta-analysis (PGC-MDD1) suggests a modest shared genetic contribution to MDD and AD. Using a (~10 fold) larger discovery sample, we calculated PRS based on the second wave (PGC-MDD2) of results, in a severe AD case–control target sample. We found significant associations between AD disease status and MDD-PRS derived from both PGC-MDD2 (most informative P-threshold=1.0, P=0.00063, R2=0.533%) and PGC-MDD1 (P-threshold=0.2, P=0.00014, R2=0.663%) meta-analyses; the larger discovery sample did not yield additional predictive power. In contrast, calculating PRS in a MDD target sample yielded increased power when using PGC-MDD2 (P-threshold=1.0, P=0.000038, R2=1.34%) versus PGC-MDD1 (P-threshold=1.0, P=0.0013, R2=0.81%). Furthermore, when calculating PGC-MDD2 PRS in a subsample of patients with AD recruited explicitly excluding comorbid MDD, significant associations were still found (n=331; P-threshold=1.0, P=0.042, R2=0.398%). Meanwhile, in the subset of patients in which MDD was not the explicit exclusion criteria, PRS predicted more variance (n=999; P-threshold=1.0, P=0.0003, R2=0.693%). Our findings replicate the reported genetic overlap between AD and MDD and also suggest the need for improved, rigorous phenotyping to identify true shared cross-disorder genetic factors. Larger target samples are needed to reduce noise and take advantage of increasing discovery sample size.
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Project description:Genome-wide association studies (GWASs) show that genetic factors contribute to the risk of severe coronavirus disease 2019 (COVID-19) and blood analyte levels. Here, we utilize GWAS summary statistics to study the shared genetic influences (pleiotropy) between severe COVID-19 and 344 blood analytes at the genome, gene, and single-nucleotide polymorphism (SNP) levels. Our pleiotropy analyses genetically link blood levels of 71 analytes to severe COVID-19 in at least one of the three levels of investigation-suggesting shared biological mechanisms or causal relationships. Six analytes (alanine aminotransferase, alkaline phosphatase, apolipoprotein B, C-reactive protein, triglycerides, and urate) display evidence of pleiotropy with severe COVID-19 at all three levels. Causality analyses indicate that higher triglycerides levels causally increase the risk of severe COVID-19, thereby providing important support for the use of lipid-lowering drugs such as statins and fibrates to prevent severe COVID-19.
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Project description:Recently, a quantitative-trait locus (QTL) for whole blood serotonin level was identified in a genomewide linkage and association study in a founder population. Because serotonin level is a sexually dimorphic trait, in the present study, we evaluated the sex-specific genetic architecture of whole blood serotonin level in the same population. Here, we use an extended homozygosity-by-descent linkage method that is suitable for large complex pedigrees. Although both males and females have high broad heritability (H2=0.99), females have a higher additive component (h2=0.63 in females; h2=0.27 in males). Furthermore, the serotonin QTL on 17q that was identified previously in this population, integrin beta 3 (ITGB3), and a novel locus on 2q influence serotonin levels only in males, whereas linkage to a region on chromosome 6q is specific to females. Both sexes contribute to linkage signals on 12q and 16p. There were, overall, more associations meeting criteria for suggestive significance in males than in females, including those of ITGB3 and the serotonin transporter gene (5HTT). This analysis is consistent with heritable sexual dimorphism in whole blood serotonin levels resulting from the effects of a combination of sex-specific and sex-independent loci.
| S-EPMC1196431 | biostudies-literature
Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity.MethodsThe genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5 × 10-8) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative (4,336 cases & 623,902 controls).FindingsWe detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04-0·57], P = 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92-1·20], P = 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1·21, [95% CI 1·06-1·38], P = 4·24 × 10-3). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73-1·00], P = 2·99 × 10-2) .InterpretationThe strongest genetic determinant of IPF, rs35705950 at MUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors.FundingNovo Nordisk Foundation and Oak Foundation.
| S-EPMC7946355 | biostudies-literature
Project description:Background: Mutations in genes encoding sarcomere and cytoskeletal proteins are major causes of primary dilated cardiomyopathy (DCM). Likewise, ischemic myocardial injury is a major cause of secondary cardiac remodeling, which, in a subset, is severe and resembles DCM. The latter is referred to as ischemic dilated cardiomyopathy (IDCM). We postulated the presence of pathogenic and likely pathogenic variants (PVs and LPVs, respectively) in genes known to cause primary DCM might predispose the heart to severe cardiac dilatation and dysfunction post myocardial ischemic injury, i.e., IDCM. Methods: We performed whole-exome sequencing in 1,041 patients with primary DCM, 215 patients with IDCM, and 414 healthy controls. Indices of cardiac size and function were similar between those with primary and ischemic DCM. PVs and LPVs, including the truncating variants in 36 genes known to cause primary DCM were identified and compared among the three groups. Results: Pathogenic variants and LPVs were detected in 266 individuals, comprised of 215/1,041 (20.7%) patients with DCM, 27/215 (12.6%) patients with IDCM, and 24/414 (5.8%) control individuals. PVs and LPVs in the TTN gene were the most common and detected in 130/1,041 (12.5%) of patients with DCM, 15/215 (7.0%) of cases with IDCM, and 10/414 (2.4%) control individuals. Of 135 TTNtv, 118 involved exons that were >90% spliced in. These variants were found in 120/1,041 (11.5%) of DCM patients, 6/215 (2.8%) of IDCM cases, and only in 1/414 (0.2%) of the control population (p < 0.001 among the three groups). Conclusions: Pathogenic variants and LPVs in genes known to cause primary DCM are enriched in patients with IDCM, suggesting that such variants function as susceptibility alleles for cardiac dilatation and dysfunction in post myocardial ischemic injury. Thus, IDCM shares a partial genetic etiology with the primary DCM.
| S-EPMC10236477 | biostudies-literature