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DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.
Richard, MA, Huan, T, Ligthart, S, Gondalia, R, Jhun, MA, Brody, JA, Irvin, MR, Marioni, R, Shen, J, Tsai, PC, et al
American journal of human genetics. 2017;(6):888-902
Abstract
Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.
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Circulating Nesfatin-1 Levels and Type 2 Diabetes: A Systematic Review and Meta-Analysis.
Zhai, T, Li, SZ, Fan, XT, Tian, Z, Lu, XQ, Dong, J
Journal of diabetes research. 2017;:7687098
Abstract
The role of nesfatin-1 in glucose homeostasis has been investigated previously. However, although numerous studies have examined the relationships between circulating nesfatin-1 levels and type 2 diabetes, the conclusions are contradictory. We aimed to probe the relationship between circulating nesfatin-1 levels and type 2 diabetes by meta-analysis. Seven studies including 328 type 2 diabetes patients and 294 control subjects were included. Although there was no obvious difference in circulating nesfatin-1 levels between patients with type 2 diabetes and the control group (MD = -0.04; 95% CI = -0.32 to -0.23), subgroup analysis showed higher nesfatin-1 levels in newly diagnosed type 2 diabetes patients (MD = 0.59; 95% CI = 0.45 to 0.74) and significantly lower nesfatin-1 levels in type 2 diabetes patients receiving antidiabetic treatment (MD = -0.26; 95% CI = -0.33 to -0.20). In conclusion, the analysis supports a relationship between circulating nesfatin-1 levels and type 2 diabetes, where newly diagnosed type 2 diabetes was associated with an elevated Nesfatin-1 level, and type 2 diabetes patients receiving antidiabetic treatment showed lower circulating nesfatin-1 levels.
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Assessment of the association between ZBTB20 rs9841504 polymorphism and gastric and esophageal cancer susceptibility: a meta-analysis.
Shi, J, Li, W, Ding, X
The International journal of biological markers. 2017;(1):e96-e101
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Abstract
BACKGROUND The protein encoded by ZBTB20 is a member of the POK family, whose members function as transcriptional repressors through interactions mediated by their conserved C2H2 Krüppel-type zinc finger and BTB/POZ domains. Polymorphisms in ZBTB20 appeared to be associated with gastric and esophageal cancer susceptibility in biological models, but the results of these studies were inconclusive. Therefore, we conducted a meta-analysis by pooling all available data to assess the exact association between the ZBTB20 rs9841504 polymorphism and gastric and esophageal cancer susceptibility. METHOD The meta-analysis was performed for homozygote comparison, heterozygote comparison, and dominant and recessive models by applying a fixed- or random-effects model. The pooled odds ratios (ORs) with the corresponding confidence intervals (CIs) were calculated. Moreover, the data were analyzed using the Stata 12.0 software(StataCorp). RESULT A total of 8 independent case-control studies comprising 9,994 cases and 10,258 controls were included. We found a significant association between the rs9841504 polymorphism and decreased gastric cancer susceptibility in the allelic, homozygous, dominant and recessive models (B vs. A:OR = 0.797, 95% CI 0.644-0.986, p = 0.036; BB vs. AA:OR = 0.601, 95% CI 0.366-0.988, p = 0.045; BA + BB vs. AA:OR = 0.789, 95% CI 0.627-0.992, p = 0.043; BB vs. BA + AA:OR = 0.635, 95% CI 0.405-0.997, p = 0.049). Conversely, no association between the rs9841504 polymorphism and esophageal cancer susceptibility was found. In subgroup analysis by ethnicity, we observed a significantly decreased susceptibility to gastric cancer in Asian populations in the allele contrast, homozygous and recessive models (B vs. A:OR = 0.791, 95% CI 0.628-0.996, p = 0.046; BB vs. AA:OR = 0.559, 95% CI 0.323-0.966, p = 0.037; BB vs. BA + AA:OR = 0.593, 95% CI 0.361-0.972, p = 0.038). CONCLUSIONS In summary, our work suggests that the ZBTB20 rs9841504 polymorphism is a protective factor for gastric cancer rather than esophageal cancer.
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Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis.
Chen, LS, Baker, T, Hung, RJ, Horton, A, Culverhouse, R, Hartz, S, Saccone, N, Cheng, I, Deng, B, Han, Y, et al
EBioMedicine. 2016;:219-226
Abstract
BACKGROUND Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. METHODS Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N=12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium. RESULTS Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR=0.48, 95%CI=0.30-0.75, p=0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR=0.68, 95%CI=0.61-0.77, p=4.9∗10-10). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype. CONCLUSION We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke.
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Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium.
Li, Q, Wojciechowski, R, Simpson, CL, Hysi, PG, Verhoeven, VJ, Ikram, MK, Höhn, R, Vitart, V, Hewitt, AW, Oexle, K, et al
Human genetics. 2015;(2):131-46
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Abstract
To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
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Resequencing and association analysis of coding regions at twenty candidate genes suggest a role for rare risk variation at AKAP9 and protective variation at NRXN1 in schizophrenia susceptibility.
Suárez-Rama, JJ, Arrojo, M, Sobrino, B, Amigo, J, Brenlla, J, Agra, S, Paz, E, Brión, M, Carracedo, Á, Páramo, M, et al
Journal of psychiatric research. 2015;:38-44
Abstract
A fraction of genetic risk to develop schizophrenia may be due to low-frequency variants. This multistep study attempted to find low-frequency variants of high effect at coding regions of eleven schizophrenia susceptibility genes supported by genome-wide association studies (GWAS) and nine genes for the DISC1 interactome, a susceptibility gene-set. During the discovery step, a total of 125 kb per sample were resequenced in 153 schizophrenia patients and 153 controls from Galicia (NW Spain), and the cumulative role of low-frequency variants at a gene or at the DISC1 gene-set were analyzed by burden and variance-based tests. Relevant results were meta-analyzed when appropriate data were available. In addition, case-only putative damaging variants were genotyped in a further 419 cases and 398 controls. The discovery step revealed a protective effect of rare missense variants at NRXN1, a result supported by meta-analysis (OR = 0.67, 95% CI: 0.47-0.94, P = 0.021, based on 3848 patients and 3896 controls from six studies). The follow-up step based on case-only putative damaging variants revealed a promising risk variant at AKAP9. This variant, K873R, reached nominal significance after inclusion of 240 additional Spanish controls from databases. The variant, located in an ADCY2 binding region, is absent from large public databases. Interestingly, GWAS revealed an association between common ADCY2 variants and bipolar disorder, a disorder with considerable genetic overlap with schizophrenia. These data suggest a role of rare missense variants at NRXN1 and AKAP9 in schizophrenia susceptibility, probably related to alteration of the excitatory/inhibitory synaptic balance, deserving further investigation.
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Integrated genomic approaches identify major pathways and upstream regulators in late onset Alzheimer's disease.
Li, X, Long, J, He, T, Belshaw, R, Scott, J
Scientific reports. 2015;:12393
Abstract
Previous studies have evaluated gene expression in Alzheimer's disease (AD) brains to identify mechanistic processes, but have been limited by the size of the datasets studied. Here we have implemented a novel meta-analysis approach to identify differentially expressed genes (DEGs) in published datasets comprising 450 late onset AD (LOAD) brains and 212 controls. We found 3124 DEGs, many of which were highly correlated with Braak stage and cerebral atrophy. Pathway Analysis revealed the most perturbed pathways to be (a) nitric oxide and reactive oxygen species in macrophages (NOROS), (b) NFkB and (c) mitochondrial dysfunction. NOROS was also up-regulated, and mitochondrial dysfunction down-regulated, in healthy ageing subjects. Upstream regulator analysis predicted the TLR4 ligands, STAT3 and NFKBIA, for activated pathways and RICTOR for mitochondrial genes. Protein-protein interaction network analysis emphasised the role of NFKB; identified a key interaction of CLU with complement; and linked TYROBP, TREM2 and DOK3 to modulation of LPS signalling through TLR4 and to phosphatidylinositol metabolism. We suggest that NEUROD6, ZCCHC17, PPEF1 and MANBAL are potentially implicated in LOAD, with predicted links to calcium signalling and protein mannosylation. Our study demonstrates a highly injurious combination of TLR4-mediated NFKB signalling, NOROS inflammatory pathway activation, and mitochondrial dysfunction in LOAD.
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Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans.
Del-Aguila, JL, Beitelshees, AL, Cooper-Dehoff, RM, Chapman, AB, Gums, JG, Bailey, K, Gong, Y, Turner, ST, Johnson, JA, Boerwinkle, E
The pharmacogenomics journal. 2014;(1):35-40
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Abstract
Hydrochlorothiazide (HCTZ) is one of the most widely prescribed antihypertensive medications. Although it is well known that HCTZ is associated with hyperglycemia and hypertriglyceridemia, the mechanisms underlying these adverse effects are not well understood. We performed a genome-wide association study and meta-analysis of the change in fasting plasma glucose and triglycerides in response to HCTZ from two different clinical trials: the Pharmacogenomic Evaluation of Antihypertensive Responses and the Genetic Epidemiology of Responses to Antihypertensive studies. Two single-nucleotide polymorphisms (rs12279250 and rs4319515 (r(2)=0.73)), located at 11p15.1 in the NELL1 gene, achieved genome-wide significance for association with change in fasting plasma triglycerides in African Americans, whereby each variant allele was associated with a 28 mg dl(-1) increase in the change in triglycerides. NELL1 encodes a cytoplasmic protein that contains epidermal growth factor-like repeats and has been shown to represses adipogenic differentiation. These findings may represent a novel mechanism underlying HCTZ-induced adverse metabolic effects.
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Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.
Leblond, CS, Nava, C, Polge, A, Gauthier, J, Huguet, G, Lumbroso, S, Giuliano, F, Stordeur, C, Depienne, C, Mouzat, K, et al
PLoS genetics. 2014;(9):e1004580
Abstract
SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.
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The genetic polymorphisms of intercellular cell adhesion molecules and breast cancer susceptibility: a meta-analysis.
Liu, L, Sun, M, Song, D, Wang, Z
Molecular biology reports. 2013;(2):1855-60
Abstract
Intercellular cell adhesion molecules (ICAMs) genetic polymorphisms have been considered to be implicated in the development of breast cancer. However, the previous reports are conflicting. Therefore, we performed a meta-analysis to assess the association between three polymorphisms, including ICAM1 K469E, ICAM5 V301I, ICAM5 rs281439, and breast cancer risk. The meta-analyses are based on a literature search of PubMed, CNKI and VIP database up until August 2011. Pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated using review manager 5.0.25 package. In total, five populations (2,020 cases and 2,012 controls) on ICAM1 K469E polymorphism, four populations (1,797 cases and 2,244 controls) on ICAM5 V301I polymorphism and five populations (2,744 cases and 3,006 controls) on ICAM5 rs281439 variant were included. Overall, the meta-analysis showed no significant association between ICAM1 K469E polymorphism and breast cancer risk. However, a significant association was observed for ICAM5 V301I polymorphism (VV vs. II: OR = 1.48, 95 % CI 1.04-2.13, P = 0.03; VV/VI vs. II: OR = 1.25, 95 % CI 1.05-1.48, P = 0.01). In addition, there was a significant association between ICAM5 rs281439 variant and breast cancer risk (GG vs. CC: OR = 1.31, 95 % CI 1.03-1.65, P = 0.03). Our meta-analysis suggests that the ICAM5 V301I and rs281439 variants but not ICAM1 K469E polymorphism may contribute to the susceptibility of breast cancer. Given the limited sample sizes, further investigation is needed.