Potential Novel Genes for Late-Onset Alzheimer’s Disease in East-Asian Descent Identified by APOE-Stratified Genome-Wide Association Study

Kang, Sarang; Gim, Jungsoo; Lee, Jiwoon; Gunasekaran, Tamil Iniyan; Choi, Kyu Yeong; Lee, Jang Jae; Seo, Eun Hyun; Ko, Pan Woo; Chung, Ji Yeon; Choi, Su Mi; Lee, Young Min; Jeong, Jee Hyang; Park, Kyung Won; Song, Min Kyung; Lee, Ho Won; Kim, Ki Woong; Choi, Seong Hye; Lee, Dong Hoon; Kim, SangYun; Kim, Hoowon; Kim, Byeong C.; Ikeuchi, Takeshi; Lee, Kun Ho

doi:10.3233/jad-210145

Cited by 25 publications

(21 citation statements)

References 45 publications

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“…This is the first meta-analysis to establish a significant association between ALDH2 * 2 and LOAD in the Asian population. Although none of the recent genome wide association studies using Caucasian samples [ 46 ] or Asian samples [ 47, 48 ] detected genome-wide significance of the ALDH2 gene, this analysis suggested that ALDH2 * 2 has some role in the pathogenesis of LOAD in the Asian population. Interestingly, a recent genome-wide associated study in a Han Chinese population showed that ALDH2 * 2 was associated with serum uric acid by affecting alcohol consumption [ 49 ].…”

Section: Discussionmentioning

confidence: 69%

Association Study and Meta-Analysis of Polymorphisms and Blood mRNA Expression of the ALDH2 Gene in Patients with Alzheimer’s Disease

Ueno

Yoshino

Mori

et al. 2022

JAD

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Background: Late-onset Alzheimer’s disease (LOAD) is a complex disease in which neuroinflammation plays an important pathophysiological role, and exposure to neurotoxic substrates such as aldehydes may contribute. Blood mRNA expression levels of neuroinflammation-related genes appear to be potential biological markers of LOAD. A relationship between ALDH2 and LOAD has been suggested. Objective: Our objective was to examine blood ALDH2 expression in Japanese LOAD patients, conduct a genetic association study, and add new studies to an extended meta-analysis of the Asian population. Methods: A blood expression study (45 AD subjects, 54 controls) in which total RNA was isolated from whole peripheral blood samples and ALDH2 expression measured was conducted. In addition, a genetic association study (271 AD subjects, 492 controls) using genomic DNA from whole peripheral blood samples was conducted. Finally, a meta-analysis examined the relationship between ALDH2*2 frequency and the risk of LOAD. Results: ALDH2 mRNA expression was significantly higher in LOAD than in controls, and also higher in men with LOAD than in women with LOAD (p = 0.043). The genotypes in the two classified groups and the allele frequency were significantly different between AD and control subjects. The meta-analysis showed a significant difference in the ALDH2*2 allele, with an increased AD risk (OR = 1.38; 95% CI = 1.02–1.85; p = 0.0348, I2 = 81.1%). Conclusion: There was a significant increase in blood ALDH2 expression, and a genetic association with ALDH2*2 in LOAD. ALDH2 may have significant roles in the pathogenesis of LOAD in the Asian population.

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Section: Discussionmentioning

confidence: 69%

Association Study and Meta-Analysis of Polymorphisms and Blood mRNA Expression of the ALDH2 Gene in Patients with Alzheimer’s Disease

Ueno

Yoshino

Mori

et al. 2022

JAD

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“…The GO term analyses of synergistically and non-synergistically expressed genes also verified these findings, as synergistic genes enriched pathways related to toxic protein response and glial cell differentiation pathways, while non-synergistic genes enriched the processes related to neurogenesis, neurotransmitter release, or RNA processing ( Figure 7 B). LRIG1 was recently identified in an AD GWAS of east Asian ancestry [ 101 ], and the gene encodes a transmembrane protein that controls the extent of the epidermal growth factor signaling by suppressing the EGF receptor (EGFR) availability [ 102 ]. EGF signaling is important for astroglial activation and priming for neurogenesis [ 50 ], and therefore upregulation of LRIG1 in human AD (logFC = 0.882, p = 0.0087) and downregulation in zebrafish (logFC = −0.353, p = 4.1 × 10 −6 ) can point towards a differential neurogenesis response in humans and zebrafish.…”

Section: Discussionmentioning

confidence: 99%

Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer’s Disease

Coşacak

Bhattarai

Jager

et al. 2022

Cells

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Neurogenesis is significantly reduced in Alzheimer’s disease (AD) and is a potential therapeutic target. Contrary to humans, a zebrafish can regenerate its diseased brain, and thus is ideal for studying neurogenesis. To compare the AD-related molecular pathways between humans and zebrafish, we compared single cell or nuclear transcriptomic data from a zebrafish amyloid toxicity model and its controls (N = 12) with the datasets of two human adult brains (N = 10 and N = 48 (Microglia)), and one fetal brain (N = 10). Approximately 95.4% of the human and zebrafish cells co-clustered. Within each cell type, we identified differentially expressed genes (DEGs), enriched KEGG pathways, and gene ontology terms. We studied synergistic and non-synergistic DEGs to point at either common or uniquely altered mechanisms across species. Using the top DEGs, a high concordance in gene expression changes between species was observed in neuronal clusters. On the other hand, the molecular pathways affected by AD in zebrafish astroglia differed from humans in favor of the neurogenic pathways. The integration of zebrafish and human transcriptomes shows that the zebrafish can be used as a tool to study the cellular response to amyloid proteinopathies. Uniquely altered pathways in zebrafish could highlight the specific mechanisms underlying neurogenesis, which are absent in humans, and could serve as potential candidates for therapeutic developments.

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“…Since the lead SNPs for these potential novel loci were absent in the East Asian dataset used for initial discovery 19 , we attempted to test these SNPs in an independent East Asian ancestry dataset 20 . We observed a nominally significant association at VWA5B2 -rs9837978 (P=0.048, β=0.204) in the GARD cohort (n=2,291), although the direction of effect was not consistent with the datasets included in the discovery GWAS.…”

Section: Resultsmentioning

confidence: 99%

Multi-ancestry meta-analysis and fine-mapping in Alzheimer’s Disease

Lake

Makarious

Kim

et al. 2022

Preprint

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Genome-wide association studies (GWAS) of Alzheimer's disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published and de novo GWAS from European, East Asian, African American, and Caribbean Hispanic populations to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer's disease to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci and globally assessed the heterogeneity of known risk factors across populations. Additionally we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to Alzheimer's disease risk.

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Potential Novel Genes for Late-Onset Alzheimer’s Disease in East-Asian Descent Identified by APOE-Stratified Genome-Wide Association Study

Cited by 25 publications

References 45 publications

Association Study and Meta-Analysis of Polymorphisms and Blood mRNA Expression of the ALDH2 Gene in Patients with Alzheimer’s Disease

Association Study and Meta-Analysis of Polymorphisms and Blood mRNA Expression of the ALDH2 Gene in Patients with Alzheimer’s Disease

Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer’s Disease

Multi-ancestry meta-analysis and fine-mapping in Alzheimer’s Disease

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