Guiyou Liu

Integrating genome-wide association studies and gene expression data highlights dysregulated multiple sclerosis risk pathways

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.

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.

Genetic variant rs763361 regulates multiple sclerosis CD226 gene expression

In a recent study, Gross et al. investigate the presence, distribution, and function of natural killer (NK) cells in three different compartments to characterize the role of NK cells in multiple sclerosis (MS) (1). Their results indicate that NK cells played an important role in controlling T-cell activity in vivo. In addition, Gross et al. found reduced expression of the activating NK-cell receptor DNAM-1 ( CD226 ) in MS. Gross et al. compare their findings to those from human genetic-association studies. Interestingly, a nonsynonymous variant, Gly307Ser (rs763361), in the CD226 gene was identified to be significantly associated with several autoimmune diseases, including MS, which further supported Gross et al.’s findings as described in their discussion (1, 2). The … [↵][1]2To whom correspondence should be addressed. Email: qhjiang{at}hit.edu.cn. [1]: #xref-corresp-1-1

Genetic Variants and Multiple Sclerosis Risk Gene SLC9A9 Expression in Distinct Human Brain Regions

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.

Cis-eQTLs regulate reduced LST1 gene and NCR3 gene expression and contribute to increased autoimmune disease risk

In PNAS, Yau et al. (1) identify a conserved 33-kb haplotype Ltab-Ncr3 across five genes, lymphotoxin-α ( Lta ), Tnf , lymphotoxin-β ( Ltb ), leukocyte-specific transcript 1 ( Lst1 ), and natural cytotoxicity-triggering receptor 3 ( Ncr3 ) in the MHC-III region in wild rats. The higher Ltb and Ncr3 expression, the lower Lst1 expression, and the expression of a shorter splice variant of Lst1 were associated with reduced arthritis severity in rats (1). Yau et al. (1) further analyzed the expression levels of LTB , LST1 , and NCR3 using whole-blood samples from 32 patients with rheumatoid arthritis (RA) and 92 healthy controls (1). They identify significantly increased expression of these three genes in RA cases (1). The mild RA cases also showed lower expression of LST1 and higher expression of … [↵][1]1To whom correspondence may be addressed. Email: hjw{at}tmu.edu.cn or qhjiang{at}hit.edu.cn. [1]: #xref-corresp-1-1

Alzheimer's disease CD33 rs3865444 variant does not contribute to cognitive performance.

Alzheimer’s disease (AD) is complex and one of the most common neurodegenerative diseases in the elderly (1). Three large-scale genome-wide association studies (GWAS) identified CD33 rs3865444 polymorphism to be significantly associated with AD susceptibility in European ancestry with genome-wide significance ( P < 5.00E-08). In our previous meta-analysis, we further confirmed the association between rs3865444 and AD susceptibility in Chinese and North American populations (1). In a recent study, Schwarz et al. analyze 13 SNPs, and identify that the … [↵][1]1To whom correspondence should be addressed. Email: qhjiang{at}hit.edu.cn. [1]: #xref-corresp-1-1

Linc-MAF-4 regulates Th1/Th2 differentiation and is associated with the pathogenesis of multiple sclerosis by targeting MAF.

In this study, we strove to substantiate the ability of linc‐MAF‐4 to act as a regulator of pathogenesis during multiple sclerosis (MS). We recruited 34 patients who were diagnosed with MS according to the revised McDonald criteria. Six patients with MS and 5 healthy volunteers contributed peripheral blood mononuclear cells for microarray analysis. Subsequent knockdown and overexpression of linc‐MAF‐4 in naive CD4+ T cells from the additional 28 patients with MS was performed to track changes in CD4+ T‐cell subsets and their function, as well as to confirm results from the prior microarray analysis. Expression of linc‐MAF‐4 increased significantly in peripheral blood mononuclear cells of patients with MS compared with those of control participants. In addition, linc‐MAF‐4 regulated encephalitogenic T helper (Th)1‐cell differentiation in patients with MS. Transfection of synthetic linc‐MAF‐4 into naive CD4+ T cells facilitated Th1‐cell differentiation and inhibited Th2‐cell differentiation by directly inhibiting MAF, which is a Th2‐cell transcription factor. Linc‐MAF‐4 also promoted activation of CD4+ T cells from patients with MS. Expression level of linc‐MAF‐4 correlated with the annual relapse rate in patients with MS. Our results suggest that linc‐MAF‐4 is involved in the pathogenesis of MS, specifically via regulation of encephalitogenic T cells.—Zhang, F., Liu, G., Wei, C., Gao, C., Hao, J. Linc‐MAF‐4 regulates Th1/Th2 differentiation and is associated with the pathogenesis of multiple sclerosis by targeting MAF. FASEB J. 31, 519–525 (2017). http://www.fasebj.org

Alzheimer’s Disease rs11767557 Variant Regulates EPHA1 Gene Expression Specifically in Human Whole Blood

Large-scale genome-wide association studies have reported EPHA1 rs11767557 variant to be associated with Alzheimers disease (AD) risk in the European population. However, it is still unclear how this variant functionally contributes to the underlying disease pathogenesis. The rs11767557 variant is located approximately 3 kb upstream of EPHA1 gene. We think that rs11767557 may modify the expression of nearby genes such as EPHA1 and further cause AD risk. Until now, the potential association between rs11767557 and the expression of nearby genes has not been reported in previous studies. Here, we evaluate the potential expression association between rs11767557 and EPHA1 using multiple large-scale eQTLs datasets in human brain tissues and the whole blood. The results show that rs11767557 variant could significantly regulate EPHA1 gene expression specifically in human whole blood. These findings may further provide important supplementary information about the regulating mechanisms of rs11767557 variant in AD risk.

Autoimmune disease variants regulate GSDMB gene expression in human immune cells and whole blood

There are four gasdermin (GSDM) proteins, including GSDMA, GSDMB, GSDMC, and GSDMD, in the human genome (1). Genome-wide association studies have reported genetic variants at 17q12.2.1 loci, including GSDMA , GSDMB , and ORDML3 genes, to be associated with kinds of autoimmune diseases, including asthma, type 1 diabetes, inflammatory bowel disease (IBD), and rheumatoid arthritis (1). However, the potential genetic mechanisms are unknown (1). In a recent study in PNAS, Chao et al. (1) identified that the GSDMB gene SNPs (rs2305479 G > A and rs2305480 C > T), which are associated with an increased susceptibility to asthma and IBD, could alter the structure of GSDMB, a sulfatide and phosphoinositide binding protein. In their discussion, Chao et al. (1) describe that GSDMB may … [↵][1]1To whom correspondence may be addressed. Email: liuguiyou1981{at}163.com or qhjiang{at}hit.edu.cn. [1]: #xref-corresp-1-1

Rs4878104 contributes to Alzheimer’s disease risk and regulates DAPK1 gene expression

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.