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.
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.
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.
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.
Background
Multiple sclerosis (MS) is a complex neurological disease and chronic inflammatory disease. Until now, observational studies have reported positive association between serum interleukin-6 ...(IL-6) levels and MS risk. In order to develop effective therapies, we should establish the causal link between IL-6 signaling and MS. However, it is currently unknown whether IL-6 signaling is causally associated with the risk of MS.
Methods
Here, we selected the increased soluble IL-6R (s-IL-6R) levels as the indirect markers for reduced IL-6 signaling, and performed a Mendelian randomization (MR) study using the rs2228145 variant as the instrumental variable to evaluate and quantify the effect of IL-6 signaling on the risk of MS. To be a comparison, we also evaluated the causal association of IL-6 signaling with the risk of other three neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).
Results
We found that the increased s-IL-6R levels (per 1 standard deviation) were significantly associated with decreased MS risk (OR = 0.96, 95% CI 0.94–0.98,
P
= 1.69E-04), but not associated with the risk of AD (OR = 1.01, 95% CI 0.92–1.11,
P
= 0.835), PD (OR = 0.94, 95% CI 0.84–1.05,
P
= 0.261), or ALS (OR = 1.00, 95% CI 0.92–1.10,
P
= 0.9411).
Conclusion
Our findings have the similar directional effects to an existing humanized anti-IL-6R monoclonal antibody Tocilizumab which could bind to the IL-6 binding site of human IL-6R and competitively inhibit IL-6 signaling. Hence, we provided genetic evidence that inhibiting the IL-6 signaling such as tocilizumab treatment might represent a novel therapy for MS.
Abstract
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.
The association between BIN1 rs744373 variant and Alzheimer's disease (AD) had been identified by genome-wide association studies (GWASs) as well as candidate gene studies in Caucasian populations. ...But in East Asian populations, both positive and negative results had been identified by association studies. Considering the smaller sample sizes of the studies in East Asian, we believe that the results did not have enough statistical power.
We conducted a meta-analysis with 71,168 samples (22,395 AD cases and 48,773 controls, from 37 studies of 19 articles). Based on the additive model, we observed significant genetic heterogeneities in pooled populations as well as Caucasians and East Asians. We identified a significant association between rs744373 polymorphism with AD in pooled populations (P = 5 × 10
, odds ratio (OR) = 1.12, and 95% confidence interval (CI) 1.07-1.17) and in Caucasian populations (P = 3.38 × 10
, OR = 1.16, 95% CI 1.10-1.22). But in the East Asian populations, the association was not identified (P = 0.393, OR = 1.057, and 95% CI 0.95-1.15). Besides, the regression analysis suggested no significant publication bias. The results for sensitivity analysis as well as meta-analysis under the dominant model and recessive model remained consistent, which demonstrated the reliability of our finding.
The large-scale meta-analysis highlighted the significant association between rs744373 polymorphism and AD risk in Caucasian populations but not in the East Asian populations.
Alzheimer's disease (AD) and Parkinson's disease (PD) are the top two common neurodegenerative diseases in elderly. Recent studies found the α-synuclein have a key role in AD. Although many clinical ...and pathological features between AD and PD are shared, the genetic association between them remains unclear, especially whether α-synuclein in PD genetically alters AD risk.
We did not obtain any significant result (OR = 0.918, 95% CI: 0.782-1.076, P = 0.291) in MR analysis between PD and AD risk. In MR between α-synuclein in PD with AD risk, we only extracted rs356182 as the IV through a strict screening process. The result indicated a significant association based on IVW method (OR = 0.638, 95% CI: 0.485-0.838, P = 1.20E-03). In order to examine the robustness of the IVW method, we used other three complementary analytical methods and also obtained consistent results.
The overall PD genetic risk factors did not predict AD risk, but the α-synuclein susceptibility genetic variants in PD reduce the AD risk. We believe that our findings may help to understand the association between them, which may be useful for future genetic studies for both diseases.
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.
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.
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.
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.
Stroke and Alzheimer’s disease (AD) are common neurological diseases. Several exiting studies indicated that late onset-AD and ischemic stroke have shared genetic links. Different kinds of stroke ...have different mechanisms. However, it remains unclear whether there is a causal relationship between different types of strokes, including any stroke (AS), any ischemic stroke (AIS), large-artery atherosclerotic stroke (LAS), and cardio-embolic stroke (CES), and AD. Herein, we conducted several Mendelian randomization (MR) studies to explore genetically causal link of different kinds of strokes and AD. The results for inverse-variance weighted (IVW) meta-analysis (β = −0.039, OR = 0.9618, and
P
-value = 0.750) and weighted median regression (WMR) (β = −0.156, OR = 0.8556, and
P
-value = 0.274) demonstrated that AS is not causally associated with AD risk. The result of MR-Egger regression (β = −1.312,
P
-value = 0.098) and intercept term (
P
-value = 0.105) illustrated no pleiotropy in this MR study. According to the results for IVW (
P
-value = 0.305, β = −0.103, and OR = 0.9021) and WMR (
P
-value = 0.487, β = −0.092, and OR = 0.9121) in the MR study between AIS and AD, there is no causal association between AIS and AD risk. In addition, the MR-Egger regression (
P
-value = 0.290 and β = −0.512) and intercept term (
P
-value = 0.387) showed no potential pleiotropy. LAS is not causally associated with AD risk according to the MR results (IVW:
P
-value = 0.568, β = 0.037, and OR = 1.0377; WMR:
P
-value = 0.793, β = −0.022, and OR = 0.9782). Additionally, the results of MR-Egger regression (
P
-value = 0.122 and β = −1.220) and intercept term (
P
-value = 0.110) showed no potential pleiotropy. Our results IVW:
P
-value = 0.245, β = −0.064, and OR = 0.938; WMR:
P
-value = 0.331, β = −0.057, and OR = 0.9446; MR-Egger:
P
-value = 0.673 and β = −0.062, and intercept term (
P
-value = 0.985) further demonstrated there is no causal link between CES and AD and no pleiotropy in this MR study. In conclusion, different types of stroke, including AS, AIS, LAS, and CES, would not be causally associated with AD risk.
Alzheimer's disease (AD) is a common neurodegenerative disease.
is the strong genetic risk factor of AD. The existing genome-wide association studies have identified many single nucleotide ...polymorphisms (SNPs) with minor effects on AD risk and the polygenic risk score (PRS) is presented to combine the effect of these SNPs. On the other hand, the volumes of various brain regions in AD patients have significant changes compared to that in normal individuals. Ch4 brain region containing at least 90% cholinergic neurons is the most extensive and conspicuous in the basal forebrain. Here, we investigated the relationship between the combined effect of AD-associated SNPs and Ch4 volume using the PRS approach. Our results showed that Ch4 volume in AD patients is significantly different from that in normal control subjects (
-value < 2.2 × 10
). AD PRS, is not associated with the Ch4 volume in AD patients, excluding the
region (
-value = 0.264) and including the
region (
-value = 0.213). However, AD best-fit PRS, excluding the
region, is associated with Ch4 volume in normal control subjects (
-value = 0.015). AD PRS based on 8070 SNPs could explain 3.35% variance of Ch4 volume. In addition, the
-value of AD PRS model in normal control subjects, including the
region, is 0.006. AD PRS based on 8079 SNPs could explain 4.23% variance of Ch4 volume. In conclusion, PRS based on AD-associated SNPs is significantly related to Ch4 volume in normal subjects but not in patients.
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
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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