A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer’s disease and gastrointestinal tract disorders
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) summ...
| Main Authors: | , , , , |
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| Format: | Journal Article |
| Language: | English |
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NATURE PORTFOLIO
2022
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| Subjects: | |
| Online Access: | http://hdl.handle.net/20.500.11937/97669 |
| _version_ | 1848766300998860800 |
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| author | Adewuyi, Emmanuel O’Brien, E.K. Nyholt, D.R. Porter, T. Laws, S.M. |
| author_facet | Adewuyi, Emmanuel O’Brien, E.K. Nyholt, D.R. Porter, T. Laws, S.M. |
| author_sort | Adewuyi, Emmanuel |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | 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 (Pmeta-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. |
| first_indexed | 2025-11-14T11:48:58Z |
| format | Journal Article |
| id | curtin-20.500.11937-97669 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T11:48:58Z |
| publishDate | 2022 |
| publisher | NATURE PORTFOLIO |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-976692025-05-03T08:15:45Z A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer’s disease and gastrointestinal tract disorders Adewuyi, Emmanuel O’Brien, E.K. Nyholt, D.R. Porter, T. Laws, S.M. Science & Technology Life Sciences & Biomedicine Biology Multidisciplinary Sciences Life Sciences & Biomedicine - Other Topics Science & Technology - Other Topics INFLAMMATORY-BOWEL-DISEASE HELICOBACTER-PYLORI MENDELIAN RANDOMIZATION SUSCEPTIBILITY LOCI GUT-MICROBIOTA RISK LOCI ASSOCIATION METAANALYSIS THERAPY AXIS Alzheimer Disease Gastroesophageal Reflux Genome-Wide Association Study Humans Membrane Proteins Nerve Tissue Proteins Polymorphism, Single Nucleotide Humans Gastroesophageal Reflux Alzheimer Disease Membrane Proteins Nerve Tissue Proteins Polymorphism, Single Nucleotide Genome-Wide Association Study 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 (Pmeta-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. 2022 Journal Article http://hdl.handle.net/20.500.11937/97669 10.1038/s42003-022-03607-2 English NATURE PORTFOLIO unknown |
| spellingShingle | Science & Technology Life Sciences & Biomedicine Biology Multidisciplinary Sciences Life Sciences & Biomedicine - Other Topics Science & Technology - Other Topics INFLAMMATORY-BOWEL-DISEASE HELICOBACTER-PYLORI MENDELIAN RANDOMIZATION SUSCEPTIBILITY LOCI GUT-MICROBIOTA RISK LOCI ASSOCIATION METAANALYSIS THERAPY AXIS Alzheimer Disease Gastroesophageal Reflux Genome-Wide Association Study Humans Membrane Proteins Nerve Tissue Proteins Polymorphism, Single Nucleotide Humans Gastroesophageal Reflux Alzheimer Disease Membrane Proteins Nerve Tissue Proteins Polymorphism, Single Nucleotide Genome-Wide Association Study Adewuyi, Emmanuel O’Brien, E.K. Nyholt, D.R. Porter, T. Laws, S.M. A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer’s disease and gastrointestinal tract disorders |
| title | A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer’s disease and gastrointestinal tract disorders |
| title_full | A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer’s disease and gastrointestinal tract disorders |
| title_fullStr | A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer’s disease and gastrointestinal tract disorders |
| title_full_unstemmed | A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer’s disease and gastrointestinal tract disorders |
| title_short | A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer’s disease and gastrointestinal tract disorders |
| title_sort | large-scale genome-wide cross-trait analysis reveals shared genetic architecture between alzheimer’s disease and gastrointestinal tract disorders |
| topic | Science & Technology Life Sciences & Biomedicine Biology Multidisciplinary Sciences Life Sciences & Biomedicine - Other Topics Science & Technology - Other Topics INFLAMMATORY-BOWEL-DISEASE HELICOBACTER-PYLORI MENDELIAN RANDOMIZATION SUSCEPTIBILITY LOCI GUT-MICROBIOTA RISK LOCI ASSOCIATION METAANALYSIS THERAPY AXIS Alzheimer Disease Gastroesophageal Reflux Genome-Wide Association Study Humans Membrane Proteins Nerve Tissue Proteins Polymorphism, Single Nucleotide Humans Gastroesophageal Reflux Alzheimer Disease Membrane Proteins Nerve Tissue Proteins Polymorphism, Single Nucleotide Genome-Wide Association Study |
| url | http://hdl.handle.net/20.500.11937/97669 |