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BACKGROUND: Alzheimer's disease (AD) is the highest risk of COVID-19 infection, hospitalization, and mortality. However, it remains largely unclear about the link between AD and COVID-19 outcomes. ACE2 is an entry receptor for SARS-CoV-2. Circulating ACE2 is a novel biomarker of death and associated with COVID-19 outcomes. METHODS: Here, we explored the shared genetics and causal association between AD and plasma ACE2 levels using large-scale genome-wide association study, gene expression, expression quantitative trait loci, and high-throughput plasma proteomic profiling datasets. RESULTS: We found a significant causal effect of genetically increased circulating ACE2 on increased risk of AD. Cross-trait association analysis identified 19 shared genetic variants, and three variants rs3104412, rs2395166, and rs3135344 at chromosome 6p21.32 were associated with COVID-19 infection, hospitalization, and severity. We mapped 19 variants to 117 genes, which were significantly upregulated in lung, spleen, and small intestine, downregulated in brain tissues, and involved in immune system, immune disease, and infectious disease pathways. The plasma proteins corresponding to LST1, AGER, TNXB, and APOC1 were predominantly associated with COVID-19 infection, ventilation, and death. CONCLUSION: Together, our findings suggest the shared genetics and causal association between AD and plasma ACE2 levels, which may partially explain the link between AD and COVID-19.
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Doença de Alzheimer , Enzima de Conversão de Angiotensina 2 , COVID-19 , Estudo de Associação Genômica Ampla , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/sangue , COVID-19/genética , COVID-19/sangue , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/sangue , SARS-CoV-2 , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Masculino , Feminino , Idoso , Predisposição Genética para Doença/genética , Biomarcadores/sangueRESUMO
Common genetic variants and susceptibility loci associated with Alzheimer's disease (AD) have been discovered through large-scale genome-wide association studies (GWAS), GWAS by proxy (GWAX) and meta-analysis of GWAS and GWAX (GWAS+GWAX). However, due to the very low repeatability of AD susceptibility loci and the low heritability of AD, these AD genetic findings have been questioned. We summarize AD genetic findings from the past 10 years and provide a new interpretation of these findings in the context of statistical heterogeneity. We discovered that only 17% of AD risk loci demonstrated reproducibility with a genome-wide significance of P < 5.00E-08 across all AD GWAS and GWAS+GWAX datasets. We highlighted that the AD GWAS+GWAX with the largest sample size failed to identify the most significant signals, the maximum number of genome-wide significant genetic variants or maximum heritability. Additionally, we identified widespread statistical heterogeneity in AD GWAS+GWAX datasets, but not in AD GWAS datasets. We consider that statistical heterogeneity may have attenuated the statistical power in AD GWAS+GWAX and may contribute to explaining the low repeatability (17%) of genome-wide significant AD susceptibility loci and the decreased AD heritability (40-2%) as the sample size increased. Importantly, evidence supports the idea that a decrease in statistical heterogeneity facilitates the identification of genome-wide significant genetic loci and contributes to an increase in AD heritability. Collectively, current AD GWAX and GWAS+GWAX findings should be meticulously assessed and warrant additional investigation, and AD GWAS+GWAX should employ multiple meta-analysis methods, such as random-effects inverse variance-weighted meta-analysis, which is designed specifically for statistical heterogeneity.
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Doença de Alzheimer , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doença de Alzheimer/genética , Humanos , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Heterogeneidade GenéticaRESUMO
The first primary age-related tauopathy (PART) genome-wide association study confirmed significant associations of Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) genetic variants with PART, and highlighted a novel genetic variant rs56405341. Here, we perform a comprehensive analysis of rs56405341. We found that rs56405341 was significantly associated with C4orf33 mRNA expression, but not JADE1 mRNA expression in multiple brain tissues. C4orf33 was mainly expressed in cerebellar hemisphere and cerebellum, and JADE1 was mainly expressed in thyroid, and coronary artery. Meanwhile, we found significantly downregulated C4orf33 expression both AD and PSP compared with normal controls, respectively.
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Doença de Alzheimer , Paralisia Supranuclear Progressiva , Tauopatias , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Paralisia Supranuclear Progressiva/genética , Paralisia Supranuclear Progressiva/metabolismo , Estudo de Associação Genômica Ampla , RNA MensageiroRESUMO
BACKGROUND: Vitamin D is an important regulator of calcium. Mendelian randomization (MR) studies exclusively focused on the circulating total 25-hydroxyvitamin D (25(OH)D) as a biomarker of vitamin D status, and have found the causal association between 25(OH)D and the risk of multiple sclerosis (MS). However, it currently remains unclear about the causal association of the 25(OH)D subtypes including 25(OH)D3 and C3-epi-25(OH)D3, as well as calcium with the risk of MS. METHODS: We performed a two-sample MR study to evaluate the causal association of circulating total 25(OH)D, 25(OH)D3, C3-epi-25(OH)D3, and calcium with the risk of MS using large-scale genome-wide association studies (GWAS) datasets from total 25(OH)D (n = 417,580), 25(OH)D3 (n = 40,562), C3-epi-25(OH)D3 (n = 40,562), calcium (n = 305,349), and MS (14,802 MS and 26,703 controls). We selected five MR methods including inverse-variance weighted (IVW), simple median, weighted median, MR-Egger, MR-PRESSO (Mendelian Randomization Pleiotropy Residual Sum and Outlier), and contamination mixture method. RESULTS: IVW showed that the genetically increased circulating 25(OH)D level (OR = 0.81, 95% CI: 0.70-0.94, P = 4.00E-03), circulating 25(OH)D3 level (OR = 0.85, 95% CI: 0.76-0.95, P = 5.00E-03), and circulating C3-epi-25(OH)D3 level (OR = 0.85, 95% CI: 0.74-0.98, P = 2.30E-02) were causally associated with reduced risk of MS. However, IVW showed no causal association between circulating calcium level and the risk of MS with OR = 2.85, 95% CI: 0.42-19.53, P = 2.85E-01. CONCLUSIONS: Our current findings together with evidence from other MR studies support the use of vitamin D but not calcium supplementation for the prevention of MS.
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Cálcio , Esclerose Múltipla , Humanos , Estudo de Associação Genômica Ampla/métodos , Esclerose Múltipla/genética , Análise da Randomização Mendeliana/métodos , Vitamina D , Cálcio da Dieta , Calcifediol , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Blood leukocyte counts (e.g., eosinophil count) are important biomarkers for the onset, classification, and exacerbation of chronic obstructive pulmonary disease (COPD). The causal relationships between them are necessary for the development of COPD treatment strategy, but remain unclear. Here, we implement two-sample bi-directional univariable Mendelian Randomization (MR) and multivariable MR to investigate the causal relationships. Univariable MR find that elevated blood eosinophil count significantly increases the risk of COPD (odds ratio (OR) = 1.22, 95% confidence interval (CI): 1.14-1.30, P = 1.54 × 10-09) and COPD-related hospitalization (OR = 1.44, 95% CI: 1.15-1.80, P = 1.36 × 10-03). Besides, it also significantly decreases the ratio of forced expiratory volume in the first second over forced vital capacity (FEV1/FVC ratio) (OR = 0.942, 95% CI: 0.914-0.971, P = 1.02 × 10-04). These findings are fully supported by multivariate MR results. Interestingly, univariable MR reveals a weak causal relationship between elevated blood eosinophil count and COPD risk in younger people (<65 years) (OR = 1.39, 95% CI: 1.10-1.75, P = 5.52 × 10-03), but not older individuals (OR = 1.20, 95% CI: 0.926-1.55, P = 0.17). Finally, reverse univariable MR reveals the onset of COPD and the decreased FEV1/FVC ratio both lead to increased blood neutrophil count (OR = 1.03, 95% CI: 1.01-1.05, P = 3.40 × 10-03 and OR = 0.947, 95% CI: 0.91-0.986, P = 8.75 × 10-03 respectively). In summary, this MR study demonstrates that high blood eosinophil count is an independent causal mediator of COPD risk, FEV1/FVC decline, and COPD-related hospitalization. The increase in neutrophil count is induced by COPD onset or FEV1/FVC decline. This suggests eosinophil, but not neutrophil, may be used as a therapeutic target for preventing the onset and exacerbation of COPD and FEV1/FVC decline. Therefore, a non-neutrophil-targeted therapeutic strategy for neutrophilic COPD is required in the future.
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Análise da Randomização Mendeliana , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/genética , Volume Expiratório Forçado , Capacidade Vital , Contagem de LeucócitosRESUMO
Background: Since 2011, three large-scale genome-wide association studies (GWAS) have confirmed that the CD2AP rs9349407 polymorphism is significantly connected with Alzheimer's disease (AD) in individuals of European descent. Subsequently, this association has been replicated in European populations, but is unclear whether it can be replicated in Chinese. Recently, the correlation between rs9349407 and AD in the Chinese population has become a research hotspot. Objective: To explore the association between rs9349407 polymorphism and AD in the Chinese population. Materials and methods: Firstly, based on the exclusion and inclusion criteria, we selected 11 independent studies from 8 articles exploring the correlation between rs9349407 variation and AD in Chinese. Secondly, we conducted a meta-analysis based on fixed and random effect models and conducted a heterogeneity test. Thirdly, we used the additive model, dominant model, and recessive model for subgroup analysis. Results: We demonstrated that the CD2AP rs9349407 polymorphism increases AD susceptibility in Chinese populations (OR = 1.33, 95% CI = 1.08-1.64, P = 7.45E-03), which is consistent with the effect observed in Caucasian populations. Additionally, subgroup analysis showed that rs9349407 under the additive model (GG + CC vs. GC, OR = 0.76, 95% CI = 0.61-0.97, P = 2.04E-02) and dominant model (GG + GC vs. CC, OR = 0.49, 95% CI = 0.32-0.74, P = 8.51E-04) were also significantly correlated with AD susceptibility, but not under the recessive model (GG vs. GC + CC, OR = 0.77, 95% CI = 0.58-1.03, P = 7.44E-02). Conclusion: These existing data suggest that rs9349307 is significantly correlated with the susceptibility to AD in the Chinese population, but future studies with large samples are needed to confirm our findings.
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BACKGROUND: Until now, both cross-sectional and longitudinal studies have identified controversial findings about the association between daytime napping and Alzheimer's disease (AD) or cognitive decline. Therefore, it remains unclear about the causal association between daytime napping and AD or cognitive decline. OBJECTIVE: We aim to investigate the causal association between daytime napping and AD. METHODS: Here, we conduct a bidirectional Mendelian randomization (MR) analysis to investigate the causal association between daytime napping and AD using large-scale GWAS datasets from daytime napping including 452,633 individuals of European ancestry and AD including 35,274 AD and 59,163 controls of European ancestry. A total of five MR methods are selected including inverse-variance weighted (IVW), weighted median, MR-Egger, MR-PRESSO, and contamination mixture method. RESULTS: MR analysis highlights significant causal association of AD with daytime napping using IVW (betaâ=â-0.006, 95% CI [-0.009, -0.002], pâ=â2.00E-03), but no significant causal association of daytime napping with AD using IVW (ORâ=â0.76, 95% CI 0.53-1.10, pâ=â1.40E-01). CONCLUSION: Our bidirectional MR analysis demonstrates the causal effect of AD on daytime napping. However, there is no causal effect of daytime napping on AD. Our current findings are consistent with recent evidence from other MR studies that highlight little evidence supporting a causal effect of sleep traits on AD and support the causal effect of AD on sleep traits.
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Doença de Alzheimer , Análise da Randomização Mendeliana , Doença de Alzheimer/genética , Estudos Transversais , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana/métodos , Polimorfismo de Nucleotídeo Único , Sono/genéticaRESUMO
BACKGROUND: Both INPP5D and INPP5F are members of INPP5 family. INPP5F rs117896735 variant was associated with Parkinson's disease (PD) risk, and INPP5D was an Alzheimer's disease (AD) risk gene. However, it remains unclear about the roles of INPP5F rs117896735 variant in AD. OBJECTIVE: We aim to investigate the roles of rs117896735 in AD. METHODS: First, we conducted a candidate variant study to evaluate the association of rs117896735 variant with AD risk using the large-scale AD GWAS dataset. Second, we conducted a gene expression analysis of INPP5F to investigate the expression difference of INPP5F in different human tissues using two large-scale gene expression datasets. Third, we conducted an expression quantitative trait loci analysis to evaluate whether rs117896735 variant regulate the expression of INPP5F. Fourth, we explore the potentially differential expression of INPP5F in AD and control using multiple AD-control gene expression datasets in human brain tissues and whole blood. RESULTS: We found that 1) rs117896735 A allele was associated with the increased risk of AD with ORâ=â1.15, 95% CI 1.005-1.315, pâ=â0.042; 2) rs117896735 A allele could increase INPP5F expression in multiple human tissues; 3) INPP5F showed different expression in different human tissues, especially in brain tissues; 4) INPP5F showed significant expression dysregulation in AD compared with controls in human brain tissues. CONCLUSION: Conclusion: We demonstrate that PD rs117896735 variant could regulate INPP5F expression in brain tissues and increase the risk of AD. These finding may provide important information about the role of rs117896735 in AD.
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Doença de Alzheimer , Doença de Parkinson , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Inositol Polifosfato 5-Fosfatases , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Mendelian-randomization (MR) studies using large-scale genome-wide association studies (GWAS) have identified causal association between educational attainment and Alzheimer's disease (AD). However, the underlying mechanisms are still required to be explored. Here, we conduct univariable and multivariable MR analyses using large-scale educational attainment, cognitive performance, intelligence and AD GWAS datasets. In stage 1, we found significant causal effects of educational attainment on cognitive performance (beta = 0.907, 95% confidence interval (CI): 0.884-0.930, P < 1.145E-299), and vice versa (beta = 0.571, 95% CI: 0.557-0.585, P < 1.145E-299). In stage 2, we found that both increase in educational attainment (odds ratio (OR) = 0.72, 95% CI: 0.66-0.78, P = 1.39E-14) and cognitive performance (OR = 0.69, 95% CI: 0.64-0.75, P = 1.78E-20) could reduce the risk of AD. In stage 3, we found that educational attainment may protect against AD dependently of cognitive performance (OR = 1.07, 95% CI: 0.90-1.28, P = 4.48E-01), and cognitive performance may protect against AD independently of educational attainment (OR = 0.69, 95% CI: 0.53-0.89, P = 5.00E-03). In stage 4, we found significant causal effects of cognitive performance on intelligence (beta = 0.907, 95% CI: 0.877-0.938, P < 1.145E-299), and vice versa (beta = 0.957, 95% CI: 0.937-0.978, P < 1.145E-299). In stage 5, we identified that cognitive performance may protect against AD independently of intelligence (OR = 0.74, 95% CI: 0.61-0.90, P = 2.00E-03), and intelligence may protect against AD dependently of cognitive performance (OR = 1.17, 95% CI: 0.40-3.43, P = 4.48E-01). Collectively, our univariable and multivariable MR analyses highlight the protective role of cognitive performance in AD independently of educational attainment and intelligence. In addition to the intelligence, we extend the mechanisms underlying the associations of educational attainment with AD.
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Doença de Alzheimer , Estudo de Associação Genômica Ampla , Humanos , Doença de Alzheimer/genética , Polimorfismo de Nucleotídeo Único , Inteligência , Escolaridade , CogniçãoRESUMO
BACKGROUND: Until now, Mendelian randomization (MR) studies have investigated the causal association of risk factors with Alzheimer's disease (AD) using large-scale AD genome-wide association studies (GWAS), GWAS by proxy (GWAX), and meta-analyses of GWAS and GWAX (GWAS+GWAX) datasets. However, it currently remains unclear about the consistency of MR estimates across these GWAS, GWAX, and GWAS+GWAX datasets. METHODS: Here, we first selected 162 independent educational attainment genetic variants as the potential instrumental variables (N = 405,072). We then selected one AD GWAS dataset (N = 63,926), two AD GWAX datasets (N = 314,278 and 408,942), and three GWAS+GWAX datasets (N = 388,324, 455,258, and 472,868). Finally, we conducted a MR analysis to evaluate the impact of educational attainment on AD risk across these datasets. Meanwhile, we tested the genetic heterogeneity of educational attainment genetic variants across these datasets. RESULTS: In AD GWAS dataset, MR analysis showed that each SD increase in years of schooling (about 3.6 years) was significantly associated with 29% reduced AD risk (OR=0.71, 95% CI: 0.60-0.84, and P=1.02E-04). In AD GWAX dataset, MR analysis highlighted that each SD increase in years of schooling significantly increased 84% AD risk (OR=1.84, 95% CI: 1.59-2.13, and P=4.66E-16). Meanwhile, MR analysis suggested the ambiguous findings in AD GWAS+GWAX datasets. Heterogeneity test indicated evidence of genetic heterogeneity in AD GWAS and GWAX datasets. CONCLUSIONS: We highlighted significant difference and genetic heterogeneity in clinically diagnosed AD GWAS and self-report proxy phenotype GWAX. Our MR findings are consistent with recent findings in AD genetic variants. Hence, the GWAX and GWAS+GWAX findings and MR findings from GWAX and GWAS+GWAX should be carefully interpreted and warrant further investigation using the AD GWAS dataset.
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Doença de Alzheimer , Estudo de Associação Genômica Ampla , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Heterogeneidade Genética , Humanos , Análise da Randomização Mendeliana , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , AutorrelatoRESUMO
Silicosis is a global occupational disease characterized by lung dysfunction, pulmonary inflammation, and fibrosis, for which there is a lack of effective drugs. Pirfenidone has been shown to exert anti-inflammatory and anti-fibrotic properties in the lung. However, whether and how pirfenidone is effective against silicosis remains unknown. Here, we evaluated the efficacy of pirfenidone in the treatment of early and advanced silicosis in an experimental mouse model and explored its potential pharmacological mechanisms. We found that pirfenidone alleviated silica-induced lung dysfunction, secretion of inflammatory cytokines (TNF-α, IL-1ß, IL-6) and deposition of fibrotic proteins (collagen I and fibronectin) in both early and advanced silicosis models. Moreover, we observed that both 100 and 200 mg/kg pirfenidone can effectively treat early-stage silicosis, while 400 mg/kg was recommended for advanced silicosis. Mechanistically, antibody array and bioinformatic analysis showed that the pathways related to IL-17 secretion, including JAK-STAT pathway, Th17 differentiation, and IL-17 pathway, might be involved in the treatment of silicosis by pirfenidone. Further in vivo experiments confirmed that pirfenidone reduced the production of IL-17A induced by silica exposure via inhibiting STAT3 phosphorylation. Neutralizing IL-17A by anti-IL-17A antibody improved lung function and reduced pulmonary inflammation and fibrosis in silicosis animals. Collectively, our study has demonstrated that pirfenidone effectively ameliorated silica-induced lung dysfunction, pulmonary inflammation and fibrosis in mouse models by inhibiting the secretion of IL-17A.
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Interleucina-17 , Pneumonia , Animais , Modelos Animais de Doenças , Fibrose , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-17/metabolismo , Janus Quinases/metabolismo , Janus Quinases/uso terapêutico , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Piridonas , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/uso terapêutico , Transdução de Sinais , Dióxido de Silício/toxicidadeRESUMO
Silicosis caused by inhalation of silica particles leads to more than ten thousand new occupational exposure-related deaths yearly. Exacerbating this issue, there are currently few drugs reported to effectively treat silicosis. Tetrandrine is the only drug approved for silicosis treatment in China, and despite more than decades of use, its efficacy and mechanisms of action remain largely unknown. Here, in this study, we established silicosis mouse models to investigate the effectiveness of tetrandrine of early and late therapeutic administration. To this end, we used multiple cardiopulmonary function test, as well as markers for inflammation and fibrosis. Moreover, using single cell RNA sequencing and transcriptomics of lung tissue and quantitative microarray analysis of serum from silicosis and control mice, our results provide a novel description of the target pathways for tetrandrine. Specifically, we found that tetrandrine attenuated silicosis by inhibiting both the canonical and non-canonical NLRP3 inflammasome pathways in lung macrophages. Taken together, our work showed that tetrandrine yielded promising results against silicosis-associated inflammation and fibrosis and further lied the groundwork for understanding its molecular targets. Our results also facilitated the wider adoption and development of tetrandirne, potentially accelerating a globally accepted therapeutic strategy for silicosis.
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Inflamassomos , Silicose , Animais , Benzilisoquinolinas , Fibrose , Inflamassomos/metabolismo , Inflamação/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Silicose/tratamento farmacológico , Silicose/metabolismoRESUMO
Abdominal aortic aneurysm (AAA) is potentially life-threatening in aging population due to the risk of aortic rupture and a lack of optimal treatment. The roles of different vascular and immune cells in AAA formation and pathogenesis remain to be future characterized. Single-cell RNA sequencing was performed on an angiotensin (Ang) II-induced mouse model of AAA. Macrophages, B cells, T cells, fibroblasts, smooth muscle cells and endothelial cells were identified through bioinformatic analyses. The discovery of multiple subtypes of macrophages, such as the re-polarization of Trem2 + Acp5 + osteoclast-like and M2-like macrophages toward the M1 type macrophages, indicates the heterogenous nature of macrophages during AAA development. More interestingly, we defined CD45+COL1+ fibrocytes, which was further validated by flow cytometry and immunostaining in mouse and human AAA tissues. We then reconstituted these fibrocytes into mice with Ang II-induced AAA and found the recruitment of these fibrocytes in mouse AAA. More importantly, the fibrocyte treatment exhibited a protective effect against AAA development, perhaps through modulating extracellular matrix production and thus enhancing aortic stability. Our study reveals the heterogeneity of macrophages and the involvement of a novel cell type, fibrocyte, in AAA. Fibrocyte may represent a potential cell therapy target for AAA.
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OBJECTIVE: Until now, observational studies have explored the impact of vitamin C intake on Alzheimer's disease (AD) risk, however, reported ambiguous findings. To develop effective therapies or prevention, the causal link between vitamin C levels and AD should be established. METHODS: Here, we selected 11 plasma vitamin C genetic variants from a large-scale plasma vitamin C GWAS dataset (N = 52,018) as the potential instrumental variables. We extracted their corresponding summary statistics from large-scale IGAP clinically diagnosed AD GWAS dataset (N = 63,926) and UK Biobank AD proxy phenotype GWAS dataset (N = 314,278), as well as two UK Biobank subgroups including the maternal AD group (27,696 cases of maternal AD and 260,980 controls) and paternal AD group (14,338 cases of paternal AD and 245,941 controls). We then performed a Mendelian randomization (MR) study to evaluate the causal association between plasma vitamin C levels and the risk of AD and AD proxy phenotype. Meanwhile, we further verified these findings using a large-scale cognitive performance GWAS dataset (N = 257,841). RESULTS: In IGAP, we found no significant causal association between plasma vitamin C levels and the risk of AD. In UK Biobank, we found that per 1 SD increase in plasma vitamin C levels (about 20.2 µmol/l) was significantly associated with the reduced risk of AD proxy phenotype (OR = 0.93, 95% CI 0.88-0.98, P = 7.00E-03). A subgroup MR analysis in UK Biobank indicated that per 1 SD increase in plasma vitamin C levels could significantly reduce the risk of AD proxy phenotype in the maternal AD group (OR = 0.89, 95% CI 0.84-0.94, P = 7.29E-05), but not in the paternal AD group (OR = 1.02, 95% CI 0.92-1.12, P = 7.59E-01). The leave-one-out permutation further showed that the SLC23A1 rs33972313 variant largely changed the precision of the overall MR estimates in all these four GWAS datasets. Meanwhile, we did not observe any significant causal effect of plasma vitamin C levels on the cognitive performance. CONCLUSION: We demonstrated that there may be no causal association between plasma vitamin C levels and the risk of AD in people of European descent. The insistent findings in clinically diagnosed AD and AD proxy phenotype may be caused by the phenotypic heterogeneity.
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BACKGROUND: Until now, epidemiological evidence regarding the association between vitamin C intake (both diet and supplements) and Parkinson's disease (PD) remains inconsistent. Hence, it is necessary to establish the causal link between vitamin C levels and PD, and further develop effective therapies or prevention. METHODS: We selected 11 newly identified plasma vitamin C genetic variants from a large-scale plasma vitamin C GWAS dataset (n = 52,018) as the effective instrumental variables, and extracted their corresponding GWAS summary statistics from PD (33,674 PD cases and 449,056 controls) and PD age at onset (AAO) (n = 28,568). We then performed a Mendelian randomization (MR) study to evaluate the causal association of plasma vitamin C levels with PD and PD AAO using inverse-variance weighted (IVW), the weighted median, MR-Egger, and MR-PRESSO test. RESULTS: We did not observe any significant association between genetically increased vitamin C levels and PD. Interestingly, we found a reduced trend of PD AAO (1.134 years) with 1 SD genetically increased vitamin C levels using IVW (beta = - 1.134, 95% CI: [- 2.515, 0.248], P = 0.108). Importantly, this trend was further successfully verified using both weighted median and MR-Egger. Each 1 SD genetically increased vitamin C levels could reduce PD AAO 1.75 and 2.592 years using weighted median (beta = - 1.750, 95% CI: [- 3.396, - 0.105], P = 0.037) and MR-Egger (beta = - 2.592, 95% CI: [- 4.623, - 0.560], P = 0.012). CONCLUSIONS: We demonstrated the causal association between genetically increased plasma vitamin C levels and reduced PD AAO in people of European descent. Randomized controlled trials are required to clarify whether diet intake or supplement, or both could reduce the AAO of PD.
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Análise da Randomização Mendeliana , Doença de Parkinson , Idade de Início , Ácido Ascórbico , Estudo de Associação Genômica Ampla , Humanos , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
We aimed to evaluate the association of PLCG2 rs72824905 variant with Alzheimer's disease (AD) and multiple sclerosis (MS) using large-scale genetic association study datasets. We selected 50,024 AD cases and 467,330 controls, and 32,367 MS cases and 36,012 controls. We found moderate heterogeneity of rs72824905 in different studies. We found significant association between rs72824905 G allele and reduced AD risk (ORâ=â0.66, 95% CI 0.59-0.74, pâ=â5.91E-14). Importantly, rs72824905 G allele could also significantly reduce the risk of MS with ORâ=â0.94, pâ=â3.63E-05. Hence, the effects of rs72824905 on AD and MS are consistent.
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Doença de Alzheimer/genética , Esclerose Múltipla/genética , Fosfolipase C gama/genética , Alelos , Doença de Alzheimer/epidemiologia , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Esclerose Múltipla/epidemiologiaRESUMO
BACKGROUND: It has been well established that the TMEM106B gene rs1990622 variant was a frontotemporal dementia (FTD) risk factor. Until recently, growing evidence highlights the role of TMEM106B in Alzheimer's disease (AD). However, it remains largely unclear about the role of rs1990622 variant in AD. METHODS: Here, we conducted comprehensive analyses including genetic association study, gene expression analysis, eQTLs analysis, and colocalization analysis. In stage 1, we conducted a genetic association analysis of rs1990622 using large-scale genome-wide association study (GWAS) datasets from International Genomics of Alzheimer's Project (21,982 AD and 41,944 cognitively normal controls) and UK Biobank (314,278 participants). In stage 2, we performed a gene expression analysis of TMEM106B in 49 different human tissues using the gene expression data in GTEx. In stage 3, we performed an expression quantitative trait loci (eQTLs) analysis using multiple datasets from UKBEC, GTEx, and Mayo RNAseq Study. In stage 4, we performed a colocalization analysis to provide evidence of the AD GWAS and eQTLs pair influencing both AD and the TMEM106B expression at a particular region. RESULTS: We found (1) rs1990622 variant T allele contributed to AD risk. A sex-specific analysis in UK Biobank further indicated that rs1990622 T allele only contributed to increased AD risk in females, but not in males; (2) TMEM106B showed different expression in different human brain tissues especially high expression in cerebellum; (3) rs1990622 variant could regulate the expression of TMEM106B in human brain tissues, which vary considerably in different disease statuses, the mean ages at death, the percents of females, and the different descents of the selected donors; (4) colocalization analysis provided suggestive evidence that the same variant contributed to AD risk and TMEM106B expression in cerebellum. CONCLUSION: Our comprehensive analyses highlighted the role of FTD rs1990622 variant in AD risk. This cross-disease approach may delineate disease-specific and common features, which will be important for both diagnostic and therapeutic development purposes. Meanwhile, these findings highlight the importance to better understand TMEM106B function and dysfunction in the context of normal aging and neurodegenerative diseases.