Liangcai Zhang

PICALM Gene rs3851179 Polymorphism Contributes to Alzheimer’s Disease in an Asian Population

PICALM gene rs3851179 polymorphism was reported to an Alzheimer’s disease (AD) susceptibility locus in a Caucasian population. However, recent studies reported consistent and inconsistent results in an Asian population. Four studies indicated no association between rs3851179 and AD in a Chinese population and one study reported weak association in a Japanese population. We consider that the failure to replicate the significant association between rs3851179 and AD may be caused by at least two reasons. The first reason may be the genetic heterogeneity in AD among different populations, and the second may be the relatively small sample size compared with large-scale GWAS in Caucasian ancestry. In order to confirm this view, in this research, we first evaluated the genetic heterogeneity of rs3851179 polymorphism in Caucasian and Asian populations. We then investigated rs3851179 polymorphism in an Asian population by a pooled analysis method and a meta-analysis method. We did not observe significant genetic heterogeneity of rs3851179 in the Caucasian and Asian populations. Our results indicate that rs3851179 polymorphism is significantly associated with AD in the Asian population by both pooled analysis and meta-analysis methods. We believe that our findings will be very useful for future genetic studies in AD.

BIN1 gene rs744373 polymorphism contributes to Alzheimer's disease in East Asian population

Large-scale genome-wide association studies (GWAS) identified BIN1 gene rs744373 polymorphism to be significantly associated with Alzheimers disease (AD) in Caucasian ancestry. Recently, this polymorphism was also investigated in East Asian population. However, no study reported significant association. We consider that the failure to replicate significant association between rs744373 polymorphism and AD may be caused by the relatively small sample size. In this research, we evaluated this association using pooled samples from previous studies (n=4982, 1437 AD cases and 3545 controls). Two methods including pooled analysis and meta-analysis were used to investigate the association. Using the pooled analysis, we observed significant association between rs744373 polymorphism and AD by both genotype test (P=3.94E-03, 4.59E-03 and 1.04E-02) and allele test (P=1.12E-03, OR=1.16, 95% CI 1.06-1.28). Interestingly, the meta-analysis confirmed this association with P=8.00E-03 (OR=1.14, 95% CI 1.03-1.25) and P=2.00E-02 (OR=1.16, 95% CI 1.02-1.32). We also evaluated the effect of rs744373 polymorphism on AD risk in different ethnic backgrounds and found that rs744373 polymorphism contributed to AD with similar genetic risk in East Asian and Caucasian populations. To our knowledge, this is the first study to show significant association between rs744373 polymorphism and AD in East Asian population.

Alzheimer's Disease Variants with the Genome-Wide Significance are Significantly Enriched in Immune Pathways and Active in Immune Cells.

The existing large-scale genome-wide association studies (GWAS) datasets provide strong support for investigating the mechanisms of Alzheimer’s disease (AD) by applying multiple methods of pathway analysis. Previous studies using selected single nucleotide polymorphisms (SNPs) with several thresholds of nominal significance for pathway analysis determined that the threshold chosen for SNPs can reflect the disease model. Presumably, then, pathway analysis with a stringent threshold to define “associated” SNPs would test the hypothesis that highly associated SNPs are enriched in one or more particular pathways. Here, we selected 599 AD variants (P < 5.00E−08) to investigate the pathways in which these variants are enriched and the cell types in which these variants are active. Our results showed that AD variants are significantly enriched in pathways of the immune system. Further analysis indicated that AD variants are significantly enriched for enhancers in a number of cell types, in particular the B-lymphocyte, which is the most substantially enriched cell type. This cell type maintains its dominance among the strongest enhancers. AD SNPs also display significant enrichment for DNase in 12 cell types, among which the top 6 significant signals are from immune cell types, including 4 B cells (top 4 significant signals) and CD14+ and CD34+ cells. In summary, our results show that these AD variants with P < 5.00E−08 are significantly enriched in pathways of the immune system and active in immune cells. To a certain degree, the genetic predisposition for development of AD is rooted in the immune system, rather than in neuronal cells.

Cell adhesion molecule pathway genes are regulated by cis-regulatory SNPs and show significantly altered expression in Alzheimer's disease brains.

We previously identified the cell adhesion molecule (CAM) pathway as a consistent signal in 2 Alzheimers 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.

Lack of association between PICALM rs3851179 polymorphism and Alzheimer's disease in Chinese population and APOEε4-negative subgroup

Recently, the association between PICALM rs3851179 polymorphism and Alzheimers disease (AD) was investigated in the Chinese population by 3 independent studies. However, both allele and genotype tests failed to reveal any association. The association was identified only in the APOEε4-negative subgroup. We think that the failure to replicate the association may be because of the relatively small sample size. In this research, we reinvestigated the association using all the samples from these 3 studies (n = 2486, and 1202 cases and 1284 control subjects). We failed to replicate this association between the rs3851179 polymorphism and AD in all samples and the APOEε4-negative subgroup. Our results indicate that rs3851179 may not be an AD susceptibility locus in the Chinese population and the APOEε4-negative subgroup.

PICALM rs3851179 Variant Confers Susceptibility to Alzheimer’s Disease in Chinese 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.

Integrating Genome-Wide Association Study and Brain Expression Data Highlights Cell Adhesion Molecules and Purine Metabolism in Alzheimer's Disease.

Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly. Recently, genome-wide association studies (GWAS) have been used to investigate AD pathogenesis. However, a large proportion of AD heritability has yet to be explained. We previously identified the cell adhesion molecule (CAM) pathway as a consistent signal in two AD GWAS. However, it is unclear whether CAM is present in the Genetic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD) GWAS and brain expression GWAS. Meanwhile, we think integrating AD GWAS and AD brain expression datasets may provide complementary information to identify important pathways involved in AD. Here, we conducted a systems analysis using (1) KEGG pathways, (2) large-scale AD GWAS from GERAD (n = 11,789), (3) two brain expression GWAS datasets (n = 399) from the AD cerebellum and temporal cortex, and (4) previous results from pathway analysis of AD GWAS. Our results indicate that (1) CAM is a consistent signal in five AD GWAS; (2) CAM is the most significant signal in AD; (3) we confirmed previous AD risk pathways related to immune system and diseases, and cardiovascular disease, etc.; and (4) we highlighted the purine metabolism pathway in AD for the first time. We believe that our results may advance our understanding of AD mechanisms and will be very informative for future genetic studies in AD.

Identifying the Association Between Alzheimer’s Disease and Parkinson’s Disease Using Genome-Wide Association Studies and Protein-Protein Interaction Network

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the first and second most common neurodegenerative diseases in the elderly. Shared clinical and pathological features have been reported. Recent large-scale genome-wide association studies (GWAS) have been conducted and reported a number of AD and PD variants. Until now, the underlying genetic mechanisms for all these newly identified PD variants as well as the association between AD and PD are still unclear exactly. We think that PD variants may contribute to AD and PD by influence on brain gene expression. Here, we conducted a systems analysis using (1) AD and PD variants (P < 5.00E−08) identified by the published GWAS; (2) four brain expression GWAS datasets using expression quantitative trait loci from the cerebellum and temporal cortex; (3) large-scale AD GWAS from the Alzheimer Disease Genetics Consortium (ADGC); (4) a protein-protein interaction network. Our results indicated that PD variants around the 17q21 were associated with gene expression and suggestive AD risk. We also identified significant interaction among AD and PD susceptibility genes. We believe that our findings may explain the underlying genetic mechanisms for newly identified PD variants in PD and AD, as well as the association between AD and PD, which may be very useful for future genetic studies for both diseases.

Measles Contributes to Rheumatoid Arthritis: Evidence from Pathway and Network Analyses of Genome-Wide Association Studies

Growing evidence from epidemiological studies indicates the association between rheumatoid arthritis (RA) and measles. However, the exact mechanism for this association is still unclear now. We consider that the strong association between both diseases may be caused by shared genetic pathways. We performed a pathway analysis of large-scale RA genome-wide association studies (GWAS) dataset with 5,539 cases and 20,169 controls of European descent. Meanwhile, we evaluated our findings using previously identified RA loci, protein-protein interaction network and previous results from pathway analysis of RA and other autoimmune diseases GWAS. We confirmed four pathways including Cytokine-cytokine receptor interaction, Jak-STAT signaling, T cell receptor signaling and Cell adhesion molecules. Meanwhile, we highlighted for the first time the involvement of Measles and Intestinal immune network for IgA production pathways in RA. Our results may explain the strong association between RA and measles, which may be caused by the shared genetic pathway. We believe that our results will be helpful for future genetic studies in RA pathogenesis and may significantly assist in the development of therapeutic strategies.

Pathway analysis of genome-wide association study and transcriptome data highlights new biological pathways in colorectal cancer

Colorectal cancer (CRC) is a common malignancy that meets the definition of a complex disease. Genome-wide association study (GWAS) has identified several loci of weak predictive value in CRC, however, these do not fully explain the occurrence risk. Recently, gene set analysis has allowed enhanced interpretation of GWAS data in CRC, identifying a number of metabolic pathways as important for disease pathogenesis. Whether there are other important pathways involved in CRC, however, remains unclear. We present a systems analysis of KEGG pathways in CRC using (1) a human CRC GWAS dataset and (2) a human whole transcriptome CRC case–control expression dataset. Analysis of the GWAS dataset revealed significantly enriched KEGG pathways related to metabolism, immune system and diseases, cellular processes, environmental information processing, genetic information processing, and neurodegenerative diseases. Altered gene expression was confirmed in these pathways using the transcriptome dataset. Taken together, these findings not only confirm previous work in this area, but also highlight new biological pathways whose deregulation is critical for CRC. These results contribute to our understanding of disease-causing mechanisms and will prove useful for future genetic and functional studies in CRC.