Genome‐wide transcriptome analysis identifies novel dysregulated genes implicated in Alzheimer's pathology

Nho, Kwangsik; Nudelman, Kelly; Allen, Mariet; Hodges, Angela; Kim, Sungeun; Risacher, Shannon L.; Apostolova, Liana G.; Lin, Kuang; Lunnon, Katie; Wang, Xue; Burgess, Jeremy D.; Ertekin-Taner, Nilüfer; Petersen, Ronald C.; Wang, Lisu; Qi, Zhenhao; He, Aiqing; Neuhaus, Isaac M.; Patel, Vishal; Foroud, Tatiana; Faber, Kelley; Lovestone, Simon; Simmons, Andrew; Weiner, Michael W.; Saykin, Andrew J.

doi:10.1002/alz.12092

Cited by 33 publications

(26 citation statements)

References 89 publications

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“…PC also appear to play a role in vascular inflammatory mediation of early AD. Recently identified risk genes CD46, encoding a serine protease which mediates inactivation of complement proteins, and IRAK3, encoding a homeostatic mediator of innate immune responses 53 were upregulated and downregulated, respectively, in PC.…”

Section: Discussionmentioning

confidence: 99%

Single nuclear transcriptional signatures of dysfunctional brain vascular homeostasis in Alzheimer’s disease

Tsartsalis

Fancy

Smith

et al. 2021

Preprint

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Brain perfusion and normal blood brain barrier integrity are reduced early in Alzheimer’s disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and control brains to characterise pathological transcriptional signatures. We found that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. EC transcriptional signatures identified mechanisms for impaired β-amyloid clearance. Evidence for immune activation was found with upregulation of interferon signalling genes in EC and in pericytes (PC). Transcriptional signatures suggested dysregulation of vascular homeostasis and angiogenesis with upregulation of pro-angiogenic signals (HIF1A) and metabolism in EC, but downregulation of homeostatic growth factor pathways (VEGF, EGF, insulin) in EC and PC and of extracellular matrix genes in fibroblasts (FB). Our genomic dissection of vascular cell risk gene enrichment suggests a potentially causal role for EC and defines transcriptional signatures associated with microvascular dysfunction in AD.

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Section: Discussionmentioning

confidence: 99%

Single nuclear transcriptional signatures of dysfunctional brain vascular homeostasis in Alzheimer’s disease

Tsartsalis

Fancy

Smith

et al. 2021

Preprint

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“…Other identified independent genome-wide significant SNPs and loci mapped to genes including CD46, SEMA3F, HLA-DRA, MTSS2, PHB, and APOE. The CD46 gene is a complement regulator which is bactericidal to Helicobacter (H) pylori 39 and was also recently identified to be associated with AD in a transcriptome analysis 40 , making it a plausible candidate in both AD and GIT disorders.…”

Section: Discussionmentioning

confidence: 99%

Cross–trait analysis of Alzheimer’s disease and gastrointestinal tract disorders identifies shared loci highlighting immune-related and statin pathways

Adewuyi¹,

O’Brien²,

Nyholt³

et al. 2021

Preprint

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Several observational studies suggest a relationship between Alzheimer’s disease (AD) and gastrointestinal tract (GIT) disorders; however, their underlying mechanisms remain unclear. Here, we analysed several genome-wide association studies (GWAS) summary statistics (N = 34,652 – 456,327) to assess AD and GIT disorders relationships. We found a significant genetic overlap and correlation between AD and each of gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), medications for GERD or PUD (PGM), gastritis-duodenitis, irritable bowel syndrome and diverticulosis, but not inflammatory bowel disease. Our analysis suggests a partial causal association between AD and gastritis-duodenitis, diverticulosis and medication for PUD. GWAS meta-analysis identified seven loci (P < 5 × 10-8, PDE4B, CD46, SEMA3F, HLA-DRA, MTSS2, PHB, and APOE) shared by AD and PGM, six of which are novel. These loci were replicated using GERD and PUD GWAS and reinforced in gene-based analyses. Lipid metabolism, autoimmune system, lipase inhibitors, PD-1 signalling, and statin pathways were significantly enriched for AD and GIT disorders. These findings support shared genetic susceptibility in AD and GIT disorders. Lipase inhibitors and statins may provide novel therapeutic avenues for AD, GIT disorders, or their comorbidity.

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“…However, putative associations also have been suggested for other diseases including systemic lupus erythematosus [ 32 ], rheumatoid arthritis [ 33 ], asthma [ 17 ], multiple sclerosis [ 34 , 35 ], glomerulonephritides (reviewed in Ref. [ 6 ]), Alzheimer disease [ 36 ], bullous pemphigoid [ 37 ] and pregnancy-related disorders (see below and Ref. [ 38 • ]).…”

Section: Deficiency Statesmentioning

confidence: 99%

Membrane cofactor protein (MCP; CD46): deficiency states and pathogen connections

Liszewski

Atkinson

2021

Current Opinion in Immunology

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Genome‐wide transcriptome analysis identifies novel dysregulated genes implicated in Alzheimer's pathology

Cited by 33 publications

References 89 publications

Single nuclear transcriptional signatures of dysfunctional brain vascular homeostasis in Alzheimer’s disease

Single nuclear transcriptional signatures of dysfunctional brain vascular homeostasis in Alzheimer’s disease

Cross–trait analysis of Alzheimer’s disease and gastrointestinal tract disorders identifies shared loci highlighting immune-related and statin pathways

Membrane cofactor protein (MCP; CD46): deficiency states and pathogen connections

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