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Single nucleotide variants (SNVs), as important components of genetic variation, affect gene expression, function and phenotype. Mining and summarizing the spatial distribution of SNVs in diseased and normal tissues for a better understanding of their characteristics and potential roles in cell-lineage determination, aging, or disease occurrence is significant. Herein, we have developed a comprehensive spatial mutation resource stSNV (http://bio-bigdata.hrbmu.edu.cn/stSNV/index.jsp), which provides an atlas of spatial SNVs in major diseased and normal tissues of human and mouse. stSNV documents 42 202 spatial mutated genes involving 898 908 SNVs called from 730 067 spots within 450 slices from 19 diseased and 28 normal tissues. Importantly, potential characteristics of SNVs are explored and provided by analyzing the perturbation of the SNVs to gene expression, spatial communication, biological function, region-specific mutated genes, spatial mutant signatures, SNV-cell co-localization and mutation core region. All these spatial mutation data and in-depth analyses have been integrated into a user-friendly interface, visualized through intuitive tables and various image formats. Flexible tools are developed to explore co-localization among clusters, genes, cell types and SNVs in the same slice. In summary, stSNV as a valuable resource helps to dissect intra-tissue genetic heterogeneity and lays the groundwork for understanding the SNVs' biological regulatory mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: 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., Results: 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., Conclusion: 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.

Genetic association studies have identified significant association between the GAB2 rs2373115 variant and Alzheimer's disease (AD). However, it is unknown whether rs2373115 affects the regulation of nearby genes. Here, we evaluate the potential effect of rs2373115 on gene expression using multiple eQTL (expression quantitative trait loci) datasets from human brain tissues from the Mayo Clinic brain expression genome-wide association study (eGWAS), the UK Brain Expression Consortium (UKBEC), the Genotype-Tissue Expression (GTEx) project, and the Brain xQTL Serve. Our findings indicate that the rs2373115 C allele is associated with increased NARS2 expression, and both reduced and increased GAB2 expression in human tissues. Using a large-scale AD case-control expression dataset, we found increased GAB2 expression and reduced NARS2 expression in AD cases compared with controls. We believe that our findings provide important information regarding the rs2373115 variant and expression of nearby genes with respect to AD risk.

Background: Large scale association studies have found a significant association between type 2 diabetes mellitus (T2DM) and transcription factor 7-like 2 (TCF7L2) polymorphism rs7903146. However, the quality of data varies greatly, as the studies report inconsistent results in different populations. Hence, we perform this meta-analysis to give a more convincing result., Methods: The articles, published from January 1st, 2000 to April 1st, 2017, were identified by searching in PubMed and Google Scholar. A total of 56628 participants (34232 cases and 22396 controls) were included in the meta-analysis. A total of 28 studies were divided into 4 subgroups: Caucasian (10 studies), East Asian (5 studies), South Asian (5 studies) and Others (8 studies). All the data analyses were analyzed by the R package meta., Results: The significant association was observed by using the dominant model (OR = 1.41, CI = 1.36 - 1.47, p < 0.0001), recessive model (OR = 1.58, CI = 1.48 - 1.69, p < 0.0001), additive model(CT vs CC) (OR = 1.34, CI = 1.28-1.39, p < 0.0001), additive model(TT vs CC) (OR = 1.81, CI = 1.69-1.94, p < 0.0001)and allele model (OR = 1.35, CI = 1.31-1.39, p < 0.0001)., Conclusion: The meta-analysis suggested that rs7903146 was significantly associated with T2DM in Caucasian, East Asian, South Asian and other ethnicities.

A recent genome-wide association study reported a significant association between rs9828519 (G) and nonresponsiveness to interferon-beta (IFN-β) treatment and dysregulation of SLC9A9 expression in multiple sclerosis (MS) cases. We hypothesize that disease-relevant tissues are necessary to detect the effects of rs9828519-tagged SNPs on SLC9A9 expression. Here, we investigated whether SLC9A9 expression is regulated by rs9828519-tagged SNPs in human brain tissue. We used HaploReg to identify the proxy SNPs of the rs9828519 variant based on linkage disequilibrium information from the 1000 Genomes Project. We evaluated the potential association between these SNPs and SLC9A9 expression using multiple expression quantitative trait loci datasets including 10 brain regions of 134 individuals from Braineac, 2 brain regions of 773 samples from brain expression GWAS datasets, and 12 brain regions from the GTEx. We discovered differential SLC9A9 expression in different brain regions and identified 15 rs9828519-tagged SNPs that significantly regulated SLC9A9 expression only in occipital cortex, intralobular white matter, and substantia nigra. Our results advance the understanding of the involvement of SLC9A9 and rs9828519 mechanisms in MS.

In 2006, a candidate gene study reported death-associated protein kinase 1 (DAPK1) rs4878104 variant to be significantly associated with Alzheimer's disease (AD) risk. However, the following studies showed inconsistent association results. Here, we conducted an updated analysis to investigate the potential association between rs4878104 and AD using a total of 60,751 samples (20,161 AD cases and 40,590 controls). In the pooled population, the results based on the allele and genotype genetic models show that rs4878104 variant is not significantly associated with AD risk. Interestingly, we identified rs4878104 variant to be significantly associated with AD risk in American population and Chinese population in subgroup analysis. Using multiple large-scale expression quantitative trait loci datasets, we further found that rs4878104 T allele could significantly regulate increased DAPK1 expression in European population. These findings suggest that rs4878104 may contribute AD susceptibility by modifying DAPK1 expression in European population.

The association between PICALM rs3851179 variant and Alzheimer's disease (AD) has been well established by previous genome-wide association studies (GWAS) and candidate gene studies in European population. Recent studies investigated the association between PICALM rs3851179 and AD susceptibility in Chinese population. However, these studies reported consistent and inconsistent results. Here, we selected 9435 samples including 3704 AD cases and 5731 controls from previous studies and evaluated this association using a meta-analysis method for additive model. We did not observe significant genetic heterogeneity in Chinese population. Our results indicate significant association between PICALM rs3851179 and AD in Chinese population. The sensitivity analysis indicates that the association between rs3851179 and AD did not vary substantially. The regression analysis suggests no significant publication bias. In summary, this updated meta-analysis highlights the involvement of PICALM rs3851179 variant in Alzheimer's disease susceptibility in Chinese population.

A genome-wide association study identified GAB2 rs2373115 to be associated with Alzheimer's disease (AD) risk in European population. However, inconsistent results are reported in East Asian population. Here, we performed an updated analysis using 65,704 samples including 20,982 AD cases and 44,722 controls. First, we investigated the GAB2 rs2373115 variant in Asian population using 3974 AD cases and 7568 controls. To further evaluate the effect of rs2373115 in different populations, we selected 17,008 AD cases and 37,154 controls in European population. We used three genetic models, and found no significant heterogeneity in Asian population. A fixed effect model analysis showed no significant association between rs2373115 and AD in Asian population. There was no significant heterogeneity in the pooled East Asian and European populations. The fixed effect model analysis again showed no significant association between rs2373115 and AD in these pooled populations. Taken together, these findings suggest that GAB2 rs2373115 may contribute to AD susceptibility only in European population but not in East Asian population., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Much effort has been expended on identifying the genetic determinants of multiple sclerosis (MS). Existing large-scale genome-wide association study (GWAS) datasets provide strong support for using pathway and network-based analysis methods to investigate the mechanisms underlying MS. However, no shared genetic pathways have been identified to date., Objective: We hypothesize that shared genetic pathways may indeed exist in different MS-GWAS datasets., Methods: Here, we report results from a three-stage analysis of GWAS and expression datasets. In stage 1, we conducted multiple pathway analyses of two MS-GWAS datasets. In stage 2, we performed a candidate pathway analysis of the large-scale MS-GWAS dataset. In stage 3, we performed a pathway analysis using the dysregulated MS gene list from seven human MS case-control expression datasets., Results: In stage 1, we identified 15 shared pathways. In stage 2, we successfully replicated 14 of these 15 significant pathways. In stage 3, we found that dysregulated MS genes were significantly enriched in 10 of 15 MS risk pathways identified in stages 1 and 2., Conclusion: We report shared genetic pathways in different MS-GWAS datasets and highlight some new MS risk pathways. Our findings provide new insights on the genetic determinants of MS.

Recent genome-wide association studies (GWAS) reported CR1 rs3818361 polymorphism to be an Alzheimer's disease (AD) susceptibility variant in European ancestry. Three independent studies investigated this association in Chinese population. However, these studies reported weak or no significant association. Here, we reinvestigated the association using all the samples from three independent studies in Chinese population (N = 4047, 1244 AD cases and 2803 controls). We also selected three independent studies in European ancestry population (N = 11787, 3939 AD cases and 7848 controls) to evaluate the effect of rs3818361 polymorphism on AD risk in different ethnic backgrounds. In Chinese population, we did not identified significant heterogeneity using additive, recessive, and dominant genetic models. Meta-analysis showed significant association between rs3818361 and AD with P = 6.00E-03 and P = 5.00E-03. We further identified no heterogeneity of rs3818361 polymorphism between Chinese and European populations. We found that rs3818361 polymorphism contributed to AD with similar genetic risk in Chinese and European populations. In summary, this is the first study to show significant association between rs3818361 polymorphism and AD in Chinese population by a meta-analysis method. Our findings indicate that the effect of CR1 rs3818361 polymorphism on AD risk in Chinese cohorts is consistent with the increased risk observed in European AD cohorts.

Large-scale genome-wide association studies (GWAS) identified three single nucleotide polymorphisms rs11136000, rs2279590, and rs9331888 in CLU gene to be significantly associated with Alzheimer's disease (AD) in Caucasian ancestry. Both rs11136000 and rs2279590 variants were successfully replicated in Asian population. However, previous studies reported either a weak association or no association between rs9331888 polymorphism and AD in Asian population. Here, we searched the PubMed, AlzGene, and Google Scholar databases. We selected 12 independent studies that evaluated the association between the rs9331888 polymorphism and AD using a case-control design. Using an additive model, we did not identify significant heterogeneity among these 12 studies. We observed significant association between rs9331888 polymorphism and AD in pooled populations (P = 2.26E - 07, odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.06-1.14). In subgroup analysis, we did not identify significant heterogeneity in both Asian and Caucasian populations. We identified significant association in Caucasian population (P = 1.67E - 08, OR = 1.13, 95% CI 1.08-1.18) but not in East Asian population (P = 0.49, OR = 1.02, 95% CI 0.96-1.10).

Many disease-related single nucleotide polymorphisms (SNPs) have been inferred from genome-wide association studies (GWAS) in recent years. Numerous studies have shown that some SNPs located in protein-coding regions are associated with numerous diseases by affecting gene expression. However, in noncoding regions, the mechanism of how SNPs contribute to disease susceptibility remains unclear. Enhancer elements are functional segments of DNA located in noncoding regions that play an important role in regulating gene expression. The SNPs located in enhancer elements may affect gene expression and lead to disease. We presented a method for identifying liver cancer-related enhancer SNPs through integrating GWAS and histone modification ChIP-seq data. We identified 22 liver cancer-related enhancer SNPs, 9 of which were regulatory SNPs involved in distal transcriptional regulation. The results highlight that these enhancer SNPs may play important roles in liver cancer.

The early genome-wide association studies (GWAS) found a significant association between lung cancer and rs1051730 (15q25) polymorphism. However, the subsequent studies reported consistent and inconsistent results in different populations. Three meta-analysis studies were thus performed to reevaluate the association. But their results remain inconsistent. After that, some new GWAS studies reported conflicting results again. We think that the divergence of these results may be due to small-scale samples or heterogeneity among different populations. Therefore, we reevaluated the association by collecting more samples (N = 33,617 cases and 116,639 controls) from 31 studies, which incorporate 8 new studies and 23 previous studies used by one or more of the three meta-analysis studies. We observed a significant association between lung cancer and rs1051730 in pooled population by using allele (OR = 1.30, 95% CI = 1.27-1.34, P <  0.0001), dominant (OR = 1.41, 95% CI = 1.29-1.55, P < 0.0001), recessive (OR = 1.53, 95% CI = 1.42-1.65, P < 0.0001) and additive (OR = 1.75, 95% CI = 1.61-1.90, P < 0.0001) models. Through the subgroup analysis, we observed a significant heterogeneity only in East Asian population (P = 0.006, I(2) = 66.9%), and the association is significant in all subgroups (OR = 1.2976, 95% CI = 1.2622-1.3339 (European ancestry), OR = 1.5025, 95% CI = 1.2465-1.8110 (African), OR = 1.7818, 95% CI = 1.3915-2.2815 (East Asian), P < 0.0001). We believe that these results will contribute to understanding the genetic mechanism of lung cancer.

We previously identified the cell adhesion molecule (CAM) pathway as a consistent signal in 2 Alzheimer's disease (AD) genome-wide association studies (GWAS). However, the genetic mechanisms of the CAM pathway in AD are unclear. Here, we conducted pathway analysis using (1) Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathways; (2) 4 brain expression GWAS datasets; and (3) 2 whole-genome AD case-control expression datasets. Using the 4 brain expression GWAS datasets, we identified that genes regulated by cis-regulatory single-nucleotide polymorphisms (SNPs) were significantly enriched in the CAM pathway (p = 2.05E-06, p = 6.10E-07, p = 2.05E-06, and p = 1.47E-07 for each dataset). Interestingly, CAM is a significantly enriched pathway using down-regulated genes (raw p = 0.0235 and adjusted p = 0.0305) and all differentially expressed genes (raw p = 0.0105 and adjusted p = 0.0156) in dataset 5, and all differentially expressed genes (raw p = 0.0041 and adjusted p = 0.0062) in dataset 6. Collectively, our results show that CAM pathway genes are regulated by cis-regulatory SNPs and show significantly altered expression in AD. We believe that our results advance the understanding of AD mechanisms and will be useful for future genetic studies of AD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The CD33 rs3865444 polymorphism was first identified to be associated with Alzheimer's disease (AD) in European population. However, the following studies reported weak or no significant association in Chinese, Japanese, Korean, American, and Canadian populations. We think that these negative results may have been caused by either relatively small sample sizes compared with those used for the previous GWAS in European ancestry or the genetic heterogeneity of the rs3865444 polymorphism in different populations. Here, we reevaluated this association using the relatively large-scale samples from previous 27 studies (N = 86,759; 31,106 cases and 55,653 controls) by searching the PubMed, AlzGene, and Google Scholar databases. We identified significant heterogeneity and observed no significant association between the rs3865444 polymorphism and AD in pooled populations (P = 0.264, odds ratio (OR) = 0.97, 95% confidence interval (CI) 0.93-1.02). In subgroup analysis, we identified significant heterogeneity only in East Asian population and observed no significant association between the rs3865444 polymorphism and AD. We further identified significant heterogeneity and observed significant association between the rs3865444 polymorphism and AD in Chinese population. We identified no significant heterogeneity and significant association in North American and European populations. Collectively, our analysis shows that the CD33 rs3865444 polymorphism is associated with AD susceptibility in Chinese, European, and North American populations. We believe that our findings will be very useful for future genetic studies on AD.