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A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer's disease and gastrointestinal tract disorders.

ABSTRACT: Consistent with the concept of the gut-brain phenomenon, observational studies suggest a relationship between Alzheimer's disease (AD) and gastrointestinal tract (GIT) disorders; however, their underlying mechanisms remain unclear. Here, we analyse several genome-wide association studies (GWAS) summary statistics (N = 34,652-456,327), to assess the relationship of AD with GIT disorders. Findings reveal a positive significant genetic overlap and correlation between AD and gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), gastritis-duodenitis, irritable bowel syndrome and diverticulosis, but not inflammatory bowel disease. Cross-trait meta-analysis identifies several loci (P_{meta-analysis} < 5 × 10^-8) shared by AD and GIT disorders (GERD and PUD) including PDE4B, BRINP3, ATG16L1, SEMA3F, HLA-DRA, SCARA3, MTSS2, PHB, and TOMM40. Colocalization and gene-based analyses reinforce these loci. Pathway-based analyses demonstrate significant enrichment of lipid metabolism, autoimmunity, lipase inhibitors, PD-1 signalling, and statin mechanisms, among others, for AD and GIT traits. Our findings provide genetic insights into the gut-brain relationship, implicating shared but non-causal genetic susceptibility of GIT disorders with AD's risk. Genes and biological pathways identified are potential targets for further investigation in AD, GIT disorders, and their comorbidity.

SUBMITTER: Adewuyi EO

PROVIDER: S-EPMC9293965 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer's disease and gastrointestinal tract disorders.

Adewuyi Emmanuel O EO O'Brien Eleanor K EK Nyholt Dale R DR Porter Tenielle T Laws Simon M SM

Communications biology 20220718 1

Consistent with the concept of the gut-brain phenomenon, observational studies suggest a relationship between Alzheimer's disease (AD) and gastrointestinal tract (GIT) disorders; however, their underlying mechanisms remain unclear. Here, we analyse several genome-wide association studies (GWAS) summary statistics (N = 34,652-456,327), to assess the relationship of AD with GIT disorders. Findings reveal a positive significant genetic overlap and correlation between AD and gastroesophageal reflux ...[more]

PMID: 35851147

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Project description:BackgroundTo study the shared genetic structure between autoimmune diseases and B-cell acute lymphoblastic leukemia (B-ALL) and identify the shared risk loci and genes and genetic mechanisms involved.MethodsBased on large-scale genome-wide association study (GWAS) summary-level data sets, we observed genetic overlaps between autoimmune diseases and B-ALL, and cross-trait pleiotropic analysis was performed to detect shared pleiotropic loci and genes. A series of functional annotation and tissue-specific analysis were performed to determine the influence of pleiotropic genes. The heritability enrichment analysis was used to detect crucial immune cells and tissues. Finally, bidirectional Mendelian randomization (MR) methods were utilized to investigate the casual associations.ResultsOur research highlighted shared genetic mechanisms between seven autoimmune disorders and B-ALL. A total of 73 pleiotropic loci were identified at the genome-wide significance level (P < 5 × 10-8), 16 of which had strong evidence of colocalization. We demonstrated that several loci have been previously reported (e.g., 17q21) and discovered some novel loci (e.g., 10p12, 5p13). Further gene-level identified 194 unique pleiotropic genes, for example IKZF1, GATA3, IKZF3, GSDMB, and ORMDL3. Pathway analysis determined the key role of cellular response to cytokine stimulus, B cell activation, and JAK-STAT signaling pathways. SNP-level and gene-level tissue enrichment suggested that crucial role pleiotropic mechanisms involved in the spleen, whole blood, and EBV-transformed lymphocytes. Also, hyprcoloc and stratified LD score regression analyses revealed that B cells at different developmental stages may be involved in mechanisms shared between two different diseases. Finally, two-sample MR analysis determined causal effects of asthma and rheumatoid arthritis on B-ALL.ConclusionsOur research proved shared genetic architecture between autoimmune disorders and B-ALL and shed light on the potential mechanism that might involve in.

Project description:It has been reported that COVID-19 patients have an increased risk of developing IBS; however, the underlying genetic mechanisms of these associations remain largely unknown. The aim of this study was to investigate potential shared SNPs, genes, proteins, and biological pathways between COVID-19 and IBS by assessing pairwise genetic correlations and cross-trait genetic analysis. We assessed the genetic correlation between three COVID-19 phenotypes and IBS using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) methods. Two different sources of IBS data were combined using METAL, and the Multi-trait analysis of GWAS (MTAG) method was applied for multi-trait analysis to enhance statistical robustness and discover new genetic associations. Independent risk loci were examined using genome-wide complex trait analysis (GCTA)-conditional and joint analysis (COJO), multi-marker analysis of genomic annotation (MAGMA), and functional mapping and annotation (FUMA), integrating various QTL information and methods to further identify risk genes and proteins. Gene set variation analysis (GSVA) was employed to compute pleiotropic gene scores, and combined with immune infiltration algorithms, IBS patients were categorized into high and low immune infiltration groups. We found a positive genetic correlation between COVID-19 infection, COVID-19 hospitalization, and IBS. Subsequent multi-trait analysis identified nine significantly associated genomic loci. Among these, eight genetic variants were closely related to the comorbidity of IBS and COVID-19. The study also highlighted four genes and 231 proteins associated with the susceptibility to IBS identified through various analytical strategies and a stratification approach for IBS risk populations. Our study reveals a shared genetic architecture between these two diseases, providing new insights into potential biological mechanisms and laying the groundwork for more effective interventions.

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A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer's disease and gastrointestinal tract disorders.

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A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer's disease and gastrointestinal tract disorders.

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