Multiple genetic and environmental factors interact to determine an individuals predisposition to non-alcoholic fatty liver disease and its phenotypic characteristics. Association studies have found a number of alleles associated with the development of non-alcoholic steatohepatitis. Our aim was to investigate whether multiple risk-associated alleles may be present in affected monozygotic twins, indicating underlying genetic predisposition to non-alcoholic steatohepatitis. We determined the genotype of 14 candidate gene polymorphisms (at 11 unlinked loci) in a set of monozygotic twins with who presented with cirrhosis within 18 months of each other. Genotyping revealed multiple single nucleotide polymorphisms at 9 independent loci in genes PNPLA3, APOC3, GCKR, TRIB1, LYPLAL1, PPP1R3B, COL13A1, and EFCAB4B, previously implicated in contributing to non-alcoholic steatohepatitis pathogenesis. In conclusion, this case series illustrates the potential cumulative effect of multiple polymorphisms in ...

Molecular Ecology Resources (2009) doi: /j x MOLECULAR DIAGNOSTICS AND DNA TAXONOMY New single nucleotide polymorphisms in Alectoris identified using chicken genome information

Switchgrass (Panicum virgatum L.) is a warm-season perennial grass with promising potential as a bioenergy crop in the United States. However, the lack of genomic resources has slowed the development of plant lines with optimal characteristics for sustainable feedstock production. We generated high-density single nucleotide polymorphism (SNP) linkage maps using a reduced-representation sequencing approach by genotyping 231 F1 progeny of a cross between two parents of lowland ecotype from the cultivars Kanlow and Alamo. Over 350 million reads were generated and aligned, which enabled identification and ordering of 4611 high-quality SNPs. The total lengths of the resulting framework maps were 1770 cM for the Kanlow parent and 2059 cM for the Alamo parent. These maps show collinearity with maps generated with polymerase chain reaction (PCR)-based simple-sequence repeat (SSR) markers, and new SNP markers were identified in previously unpopulated regions of the genome. Transmission segregation ...

TY - JOUR. T1 - A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of erectile dysfunction following radiation therapy for prostate cancer. AU - Kerns, Sarah L.. AU - Stock, Richard. AU - Stone, Nelson. AU - Buckstein, Michael. AU - Shao, Yongzhao. AU - Campbell, Christopher. AU - Rath, Lynda. AU - De Ruysscher, Dirk. AU - Lammering, Guido. AU - Hixson, Rosetta. AU - Cesaretti, Jamie. AU - Terk, Mitchell. AU - Ostrer, Harry. AU - Rosenstein, Barry S.. PY - 2013/1/1. Y1 - 2013/1/1. N2 - Purpose: To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated with radiation therapy. Methods and Materials: A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix ...

Knowledge of genetic diversity and population structure in breeding material could be of great importance for crop improvement. Inheritance of molecular markers has been proved to be a powerful tool for verifying or discovering the parentage of cultivars in several crops. The present study aimed to undertake an extended parentage analysis using a large sample of garden asparagus (Asparagus officinalis L.) cultivars based on single nucleotide polymorphism (SNP) markers. In the past, asparagus cultivars began to be classified according to the countries and towns where they were grown. Among them, Violet Dutch is one of the oldest asparagus cultivars, considered to be the genetic stock from which several modern cultivars were derived. Starting from Violet Dutch, the breeding programs branched in two directions, yielding Argenteuil and Braunschweiger varieties in France and Germany, respectively. These lines became very important in all breeding programs, replacing older populations and landraces. ...

Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected by clinical teams after clinical examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also in only participants with pathological diagnosis. In the replication stage, we ...

Association of carriers of single nucleotide polymorphisms rs206787 and rs516535 in gene BRD2 and rs3743123 in gene GJD2 with juvenile myoclonic epilepsy of Caucasian patients in the Siberia

Kovacs, A, Green, F, Hansson, LO, Lundman, P, Samnegard, A, Boquist, S, Ericsson, CG, Watkins, HH, Hamsten, A and Tornvall, P (2005) A novel common single nucleotide polymorphism in the promoter region of the C-reactive protein gene associated with the plasma concentration of C-reactive protein ...

Skol, A. D., Scott, L. J., Abecasis, G. R. and Boehnke, M. (2007), Optimal designs for two-stage genome-wide association studies. Genet. Epidemiol., 31: 776-788. doi: 10.1002/gepi.20240 ...

Analyzing a single nucleotide polymorphism in schizophrenia: a meta-analysis approach Oluwadamilare Falola,1 Victor Chukwudi Osamor,1,2 Marion Adebiyi,1,2 Ezekiel Adebiyi1,2 1Covenant University Bioinformatics Research (CUBRe), 2Department of Computer and Information Sciences, College of Science and Technology, Covenant University, Ota, Ogun State, Nigeria Background: Schizophrenia is a severe mental disorder affecting >21 million people worldwide. Some genetic studies reported that single nucleotide polymorphism (SNP) involving variant rs1344706 from the ZNF804A gene in human beings is associated with the risk of schizophrenia in several populations. Similar results tend to conflict with other reports in literature, indicating that no true significant association exists between rs1344706 and schizophrenia. We seek to determine the level of association of this SNP with schizophrenia in the Asian population using more recent genome-wide association study (GWAS) datasets. Methods: Applying a

Clusterin (CLU; also known as apolipoprotein J, ApoJ) is a protein of inconstant structure known to be involved in diverse processes inside and outside of brain cells. CLU can act as a protein chaperon or protein solubilizer, lipid transporter as well as redox sensor and be anti- or proapoptotic, depending on context. Primary structure of CLU is encoded by CLU gene which contains single nucleotide polymorphisms (SNPs) associated with the risk of late-onset Alzheimers disease (LOAD). Studying a sample of Czech population and using the case-control association approach we identified C allele of the SNP rs11136000 as conferring a reduced risk of LOAD, more so in females than in males. Additionally, data from two smaller subsets of the population sample suggested a possible association of rs11136000 with diabetes mellitus. In a parallel study, we found no association between rs11136000 and mild cognitive impairment (MCI). Our findings on rs11136000 and LOAD contradict those of some previous ...

TY - JOUR. T1 - A genome-wide association study reveals that variants within the HLA region are associated with risk for nonobstructive azoospermia. AU - Zhao, Han. AU - Xu, Jianfeng. AU - Zhang, Haobo. AU - Sun, Jielin. AU - Sun, Yingpu. AU - Wang, Zhong. AU - Liu, Jiayin. AU - Ding, Qiang. AU - Lu, Shaoming. AU - Shi, Rong. AU - You, Li. AU - Qin, Yingying. AU - Zhao, Xiaoming. AU - Lin, Xiaoling. AU - Li, Xiao. AU - Feng, Junjie. AU - Wang, Li. AU - Trent, Jeffrey M.. AU - Xu, Chengyan. AU - Gao, Ying. AU - Zhang, Bo. AU - Gao, Xuan. AU - Hu, Jingmei. AU - Chen, Hong. AU - Li, Guangyu. AU - Zhao, Junzhao. AU - Zou, Shuhua. AU - Jiang, Hong. AU - Hao, Cuifang. AU - Zhao, Yueran. AU - Ma, Jinglong. AU - Zheng, S. Lilly. AU - Chen, Zi Jiang. PY - 2012/5/4. Y1 - 2012/5/4. N2 - A genome-wide association study of Han Chinese subjects was conducted to identify genetic susceptibility loci for nonobstructive azoospermia (NOA). In the discovery stage, 802 azoospermia cases and 1,863 controls were ...

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.s profile, publications, research topics, and co-authors

Advantages of sSNP genotyping: sSNPs afford many advantages for analysis of phylogenetic relationships among microbial strains, especially closely related clonal organisms such as the M. tuberculosis complex. Most or all sSNPs are selectively neutral and hence minimally subject to convergence, a process that can obscure or distort evolutionary relationships (Kimura 1983). Binary data are obtained, which means that the information is readily amenable to storage, retrieval, analysis by personal computers equipped with simple software, and comparison between different laboratories and studies. Importantly, the considerable biomedical interest in human SNPs (Schorket al. 2000; Dalyet al. 2001; Gut 2001; Johnsonet al. 2001) means that microbial pathogen research will benefit extensively from the ongoing development and implementation of methods to index very large numbers of SNPs efficiently, inexpensively, and automatically (Kwok 2001). Because of the many advantages of using sSNP analysis for ...

Background:Primary open angle glaucoma (POAG) is considered to be a leading cause of irreversible blindness worldwide. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) have been extensively studied as POAG risk factors. Recently, several single-nucleotide polymorphisms (SNPs) for MMPs and TIMPs encoding genes have been reported in POAG patients. The aim of this study was to investigate association of the -1607 1G/2G MMP1 and 372 T/C TIMP1 gene polymorphisms with risk of POAG in a Polish population.Material/Methods:In the present case-control study we examined a group of 449 unrelated Caucasian subjects consisting of 196 POAG patients (66 males and 130 females; mean age 70±14) and 253 controls (72 males and 181 females; mean age 67±16). The MMP1-1607 1G/2G and TIMP1 372 T/C gene polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The odds ratios (ORs) and 95% confidence intervals (CIs) for each genotype and allele were calculated

We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P 1.4 10(7)) and replicated convincingly (P 3.9 10(5)) in 798 cases and 2931 controls [per allele odds ratio (OR) 1.27 in replication cohort, P 7.7 10(11) in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P 1.7 10(7)) and replicated convincingly (P 1.2 10(5)) in 789 cases and 2927 controls (per allele OR 1.31 in replication cohort, P 3.03 10(11) in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TOF.. ...

TY - JOUR. T1 - Identification of a significant association of a single nucleotide polymorphism in TNXB with systemic lupus erythematosus in a Japanese population. AU - Kamatani, Yoichiro. AU - Matsuda, Koichi. AU - Ohishi, Tetsuya. AU - Ohtsubo, Shigeru. AU - Yamazaki, Keiko. AU - Iida, Aritoshi. AU - Hosono, Naoya. AU - Kubo, Michiaki. AU - Yumura, Wako. AU - Nitta, Kosaku. AU - Katagiri, Toyomasa. AU - Kawaguchi, Yasushi. AU - Kamatani, Naoyuki. AU - Nakamura, Yusuke. PY - 2008/1/1. Y1 - 2008/1/1. N2 - Systemic lupus erythematosus (SLE) is one of the common autoimmune diseases, with complex genetic components. Here, we report on a case-control association study of 178 SLE patients and 899 control subjects, using genome-wide gene-based single nucleotide polymorphism (SNP) markers. An SNP, rs3130342, in a 5 flanking region of the TNXB gene revealed a significant association with SLE [P = 0.000000930, odds ratio (OR) 3.11, with 95% confidence interval (95%CI) of 1.89-5.28] in a Japanese ...

Genome-wide studies of gene expression have successfully identified genetic variants that contribute to the variation of gene expression within populations [1-11]. The objective of genome-wide association studies (GWAS) is to map genotypic variation to phenotypic variation. Jansen and Nap [12] proposed extending the GWAS paradigm to deal with quantitative endophenotypes, e.g. RNA, protein and metabolite abundance in a cell. To date, consideration of RNA abundance has received most attention in the literature [1-11]. Those variants that affect gene expression are referred to as expression quantitative trait loci (eQTLs) of which thousands have been reported [1-11]. Most studies have focused on single nucleotide polymorphisms (SNPs).. The literature reports two classes of eQTL, cis-acting SNPs and trans-acting SNPs. Cis-acting SNPs lie within a gene or near the transcription start or stop site of a gene and correlate with the expression of that gene. In contrast, trans-acting SNPs can lie anywhere ...

The DENND1A gene is one of the most important sites associated with polycystic ovary syndrome (PCOS). We attempted to analyze the correlation between five single nucleotide polymorphisms (SNPs) in the DENND1A gene and the development of PCOS. A total of 346 PCOS patients and 225 normal ovulatory women were involved in the case-control study. Clinical variables and hormones were recorded. According to the Hap Map database, five tagging SNPs (rs2479106, rs2768819, rs2670139, rs2536951 and rs2479102) in the DENND1A gene were identified. The TaqMan probe and the PCR-RFLP (restriction fragment length polymorphism) methods were used for revealing these genotypes. TaqMan Genotype Software was used to analyze the alleles of the five SNPs. Linkage disequilibrium and the gene frequency analysis demonstrated that the CCGGG haplotype might increase the risk of PCOS (P = 0.038, OR = 1.89, 95% CI = 1.027-3.481). Significant differences were found in genotypic and allelic distributions at the rs2536951 and rs2479102

Genome-wide association studies (GWAS) using array-based genotyping technology are widely used to identify genetic loci associated with complex diseases or other phenotypes. The costs of GWAS projects based on individual genotyping are still comparatively high and increase with the size of study populations. Genotyping using pooled DNA samples, as also being referred as to allelotyping approach, offers an alternative at affordable costs. In the present study, data from 100 DNA samples individually genotyped with the Affymetrix Genome-Wide Human SNP Array 6.0 were used to estimate the error of the pooling approach by comparing the results with those obtained using the same array type but DNA pools each composed of 50 of the same samples. Newly developed and established methods for signal intensity correction were applied. Furthermore, the relative allele intensity signals (RAS) obtained by allelotyping were compared to the corresponding values derived from individual genotyping. Similarly, differences in

Background: Many cardiovascular diseases may require lifelong anticoagulation therapy. Warfarin is the most prescribed medication in this regard, however, it has serious side effects. Recently the new issue regarding to warfarin dosing is considered in which some single nucleotide polymorphisms (SNPs) affecting cytochrome P450 system can impact on warfarin metabolism and dosing. Methods: 230 cardiovascular patients have participated in the study. The INR levels was 1.5 - 3.5 with a mean range of 2.8. The subjects were divided into two case and control groups. The rs2108622 SNP of the CYP4F2 gene and its effect on warfarin dosing in these patients was accessed. Results: The results of our study showed a correlation between age and warfarin dosage. The overall frequency of the CC and TT allele of rs2108622 was 53.1% and 18.6%. Daily average dose of warfarin in CC, CT and TT variants was 3.5 ± 1.6, 4.5 ± 2.1 and 5.3 ± 2.1 respectively. The daily warfarin dose in patients with CC allele was

Amy J. Tucker, Branden Deschambault, and Marica Bakovic. 3.1 Introduction 45. 3.2 Nutrigenetics 46. 3.2.1 Gene polymorphisms 46. 3.2.2 Single nucleotide polymorphisms (SNPs) 47. 3.2.3 Nonsynonymous single nucleotide polymorphisms (nsSNPs) 47. 3.2.4 Regulatory single nucleotide polymorphisms (rSNPs) 48. 3.2.5 Splice site single nucleotide polymorphisms (ssSNPs) 48. 3.2.6 Trans-Acting rSNPs 48. 3.3 Complexities of chronic disease research in nutrigenetics 49. 3.4 Chronic Disease and Rare SNPs 50. 3.4.1 Copy number variants 50. 3.5 CVD and Nutrigenetics 51. 3.6 Nutrigenetics and Cancer 51. 3.7 Summary of Nutrigenetic Research Potential 51. 3.8 Nutriepigenetics 52. 3.8.1 Role of the epigenome 52. 3.8.2 Cause of epimutations 52. 3.9 Epimutations in Chronic Disease 53. 3.9.1 Epimutations and macronutrients/micronutrients 53. 3.9.2 Epimutations and phytochemicals 54. 3.10 Summary of Epigenetic Research Potential 54. 3.11 Nutrigenomics 54. 3.11.1 Genomic impact of diet 55. 3.11.2 Carbohydrates and gene ...

Nuclear factor erythroid 2-related factor 2 (Nrf2) is involved in cell proliferation by promotion of metabolic activity. It is also the major regulator of antioxidants and has a pivotal role in tumor cell proliferation and resistance to chemotherapy. Accordingly, we investigated the role of Nrf2 in renal cell carcinoma (RCC). In 50 patients who had metastatic RCC and received cytoreductive nephrectomy, we performed Nrf2 gene mutation analysis using targeted next-generation sequencing, as well as investigating a specific single nucleotide polymorphism (SNP; rs6721961) in the Nrf2 promoter region and Nrf2 protein expression. Targeted next-generation sequencing revealed that five tumors had SNPs of Nrf2 associated with amino acid sequence variation, while 11 tumors had SNPs of Kelch-like ECH-associated protein 1 gene, 35 had SNPs of von Hippel-Lindau gene, and none had SNPs of fumarate hydratase gene. The three genotypes of rs6721961 showed the following frequencies: 60% for C/C, 34% for C/A, and 6% for A

TY - JOUR. T1 - A single nucleotide polymorphism in catalase is strongly associated with ovarian cancer survival. AU - Belotte, Jimmy. AU - Fletcher, Nicole M.. AU - Saed, Mohammed G.. AU - Abusamaan, Mohammed S.. AU - Dyson, Gregory. AU - Diamond, Michael P.. AU - Saed, Ghassan M.. PY - 2015/8/24. Y1 - 2015/8/24. N2 - Ovarian cancer is the deadliest of all gynecologic cancers. Recent evidence demonstrates an association between enzymatic activity altering single nucleotide polymorphisms (SNP) with human cancer susceptibility. We sought to evaluate the association of SNPs in key oxidant and antioxidant enzymes with increased risk and survival in epithelial ovarian cancer. Individuals (n = 143) recruited were divided into controls, (n = 94): healthy volunteers, (n = 18), high-risk BRCA1/2 negative (n = 53), high-risk BRCA1/2 positive (n = 23) and ovarian cancer cases (n = 49). DNA was subjected to TaqMan SNP genotype analysis for selected oxidant and antioxidant enzymes. Of the seven selected SNP ...

Purpose: : To study the relationships between single nucleotide polymorphisms (SNPs) of extracellular matrix (ECM), matrix metalloproteases (MMPs), tissue inhibitors of MMPs (TIMPs), and other glaucoma-associated genes and primary acute primary angle closure glaucoma (PACG). Methods: : We extracted DNA samples from 47 adult patients with acute PACG and 46 controls subjects to study the relationships between these genes and acute PACG. Genotyping was performed at 35 genes by the GenomeLab SNPstream genotyping system after PCR amplification of chromosomal DNA. The association between these genetic polymorphisms and risk of primary PACG was estimated by Χ2 and logistic regression. Results: : The genotyping success rate was 99%. The genotyping for the MMP9 (rs2664538) was significantly different between the two groups (p=0.00005) and the odd ratio was 6.20 (95% CI: 2.52-15.223, p,0.00001). However, there were no associations of SNPs of other genes with acute PACG. Conclusions: : Our results reveal ...

The C1858T polymorphism in the Ptpn22 gene is associated with increased susceptibility to several autoimmune disorders including Type 1 Diabetes (T1D). This produces a gain-of-function R620W variant with diminished binding affinity to Csk, which, like PTPN22 is an inhibitor of antigen receptor signaling. In the T1D-prone BioBreeding (BB) rat, this gene is located in the Iddm3 locus on chromosome 2, making it a likely candidate gene. Sequencing revealed a non-synonymous SNP causing an A629T substitution C-terminal to the PTPN22 P1 domain that binds to Csk. Co-immunoprecipitations examining the PTPN22-Csk interaction have shown a 2-fold reduction in binding affinity of the BB compared to the ACI variant. Importantly, a genome-wide segregation analysis of an F2(BBxACI.1u.lyp) cohort revealed the dominant effect of the BB allele to confer a 3-fold increased T1D risk compared to the allele carried by the T1D-resistant ACI strain. Homozygosity for the BB allele is also associated with phenotypes ...

To identify genetic factors influencing quantitative traits of biomedical importance, we conducted a genome-wide association study in 8,842 samples from population-based cohorts recruited in Korea. For height and body mass index, most variants detected overlapped those reported in European samples. For the other traits examined, replication of promising GWAS signals in 7,861 independent Korean samples identified six previously unknown loci. For pulse rate, signals reaching genome-wide significance mapped to chromosomes 1q32 (rs12731740, P = 2.9 x 10(-9)) and 6q22 (rs12110693, P = 1.6 x 10(-9)), with the latter approximately 400 kb from the coding sequence of GJA1. For systolic blood pressure, the most compelling association involved chromosome 12q21 and variants near the ATP2B1 gene (rs17249754, P = 1.3 x 10(-7)). For waist-hip ratio, variants on chromosome 12q24 (rs2074356, P = 7.8 x 10(-12)) showed convincing associations, although no regional transcript has strong biological candidacy. Finally, we

Purpose: : To investigate the myocilin (MYOC) gene promoter polymorphism -1000C,G (MYOC mt.1) in Brazilian patients with primary open angle glaucoma (POAG) and to evaluate its possible role on the phenotype and the severity of the disease. Methods: : Eighty-nine patients with POAG and 107 normal controls enrolled the study. DNA samples were prepared and the MYOC mt.1 polymorphism in the promoter region was screened by RT - PCR in a SNP assay. Frequencies of the MYOC mt.1 promoter polymorphism were determined for both groups and compared by Fishers exact test and Chi-square test with Yates correction. Results: : MYOC mt.1 genotype frequencies did not differ in POAG and healthy subjects (P=0.328); 14.9% of control subjects and 21.3% of POAG patients were MYOC mt.1 carriers (either CG or GG). The frequency of G allele was similar between glaucoma and controls (10.8% and 7.4%, respectively; P=0.326). Among POAG patients there was no difference, according to the genotype, in intraocular pressure ...

BACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts. METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS. RESULTS: A combined GRS for atrial fibrillation, coronary artery disease

In this report, we show how a convenient on-resin copper-click functionalization of azido-functionalized peptide nucleic acids (PNAs) allows various PNA-based detection strategies. Firstly, a thiazole orange (TO) clicked PNA probe facilitates a binary readout when combined with F/Q labeled DNA, giving increased sensitivity for antisense detection. Secondly, our TO-PNA conjugate ... read more also allows single nucleotide polymorphism detection. Since antisense detection is also possible in the absence of the TO label, our sensing platform based on azido-d-ornithine containing PNA even allows for additional and more advanced functionalization and sensing strategies. show less ...

Background and Purpose - Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts. Methods - Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS. Results - A combined GRS for atrial fibrillation, coronary ...

Genome-wide association studies are set to become the method of choice for uncovering the genetic basis of human diseases. A central challenge in this area is the development of powerful multipoint methods that can detect causal variants that have not been directly genotyped. We propose a coherent analysis framework that treats the problem as one involving missing or uncertain genotypes. Central to our approach is a model-based imputation method for inferring genotypes at observed or unobserved SNPs, leading to improved power over existing methods for multipoint association mapping. Using real genome-wide association study data, we show that our approach (i) is accurate and well calibrated, (ii) provides detailed views of associated regions that facilitate follow-up studies and (iii) can be used to validate and correct data at genotyped markers. A notable future use of our method will be to boost power by combining data from genome-wide scans that use different SNP sets.

Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P | 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P= 4.3 × 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P= 8.6 × 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa

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Aims/hypothesis New genetic variants associated with susceptibility to type 2 diabetes mellitus have been discovered in recent genome-wide association (GWA) studies. The aim of the present study was...

Genome-wide association studies are important tools to reconstruct the genotype phenotype map to understand the underlying genetic architecture of complex traits. This enables us to better understand the genetic architecture of these phenotypes. With the advances in genotyping and high throughput sequencing technologies, millions of markers can be identified for individual populations in very short durations of time. Due to the multiple loci control nature of complex phenotypes, there is great interest to test markers simultaneously instead of one by one. In chapter 2, we compare three model selection methods for genome wide association studies using simulations: the Stochastic Search Variable Selection (SSVS), the Least Absolute Shrinkage and Selection Operator (LASSO) and the Elastic Net. We apply the three methods to identify genetic variants that are associated with daunorubicin-induced cytotoxicity. We also compare the LASSO and the SSVS to a dataset of two quantitative phenotypes related ...

Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium.

Introduction: Adiponectin is anti-inflammatory and anti-tumor cytokine secreted exclusively from adipocytes. Thereis a growing evidence of association between adiponectin gene polymorphism and development of pancreatic cancer.The current study aimed at evaluation of the possible association between selected adiponectin gene polymorphism andthe risk of pancreatic cancer. Methods: Prospective case-control study included 77 patients (29 women and 48 men)with biopsy-proven pancreatic adenocarcinoma and 97 healthy control. Blood samples from all included participantswere genotyped for 3 single nucleotide polymorphism (SNPs) of adiponectin genes (rs1501299C|A, rs266729C|G andrs2241766G|T) by PCR. Clinical, biochemical, and radiological data analyzed. Results: We demonstrated a significantassociation between the three studied SNPs (rs1501299, rs266729, and rs2241766) and increased risk of pancreaticadenocarcinoma (p|0.001). Furthermore, in clinical correlation analysis, Patients with rs2241766 polymorphismhave

Background: More than 60 genetic susceptibility loci associated with type 2 diabetes mellitus (T2DM) have been established in populations of Asian and European ancestry. Given ethnic differences and environmental factors, validation of the effects of genetic risk variants with reported associations identified by Genome-Wide Association Studies (GWASs) is essential. The study aims at evaluating the associations of T2DM with 29 single nucleotide polymorphisms (SNPs) from 19 candidate genes derived from GWASs in a northern Han Chinese population. Method: In this case-control study, 461 T2DM-diagnosed patients and 434 controls were recruited at the Jidong oil field hospital (Hebei, China) from January 2009 to October 2013. A cumulative genetic risk score (cGRS) was calculated by summation of the number of risk alleles, and a weight GRS (wGRS) was calculated as the sum of risk alleles at each locus multiplied by their effect sizes for T2DM, using the independent variants selected. Result: The allelic

OBJECTIVE: Recent genome-wide association studies have resulted in a dramatic increase in our knowledge of the genetic loci involved in type 2 diabetes. In a complementary approach to these single-marker studies, we attempted to identify biological pathways associated with type 2 diabetes. This approach could allow us to identify additional risk loci. RESEARCH DESIGN AND METHODS: We used individual level genotype data generated from the Wellcome Trust Case Control Consortium (WTCCC) type 2 diabetes study, consisting of 393,143 autosomal SNPs, genotyped across 1,924 case subjects and 2,938 control subjects. We sought additional evidence from summary level data available from the Diabetes Genetics Initiative (DGI) and the Finland-United States Investigation of NIDDM Genetics (FUSION) studies. Statistical analysis of pathways was performed using a modification of the Gene Set Enrichment Algorithm (GSEA). A total of 439 pathways were analyzed from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology,

AbstractMultilocus haplotype analysis of candidate variants with genome wide association studies (GWAS) data may provide evidence of association with disease, even when the individual loci themselves do not. Unfortunately, when a large number of candidate variants are investigated, identifying risk haplotypes can be very difficult. To meet the challenge, a number of approaches have been put forward in recent years. However, most of them are not directly linked to the disease-penetrances of haplotypes and thus may not be efficient. To fill this gap, we propose a mixture model-based approach for detecting risk haplotypes. Under the mixture model, haplotypes are clustered directly according to their estimated disease penetrances. A theoretical justification of the above model is provided. Furthermore, we introduce a hypothesis test for haplotype inheritance patterns which underpin this model. The performance of the proposed approach is evaluated by simulations and real data analysis. The results show that

Background: Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function. Objective: We conducted the first genome-wide association study on the age-related decrease in FEV1 and its ratio to forced vital capacity (FVC) stratified a priori by asthma status.

In spite of the common belief of Europe as reasonably homogeneous at genetic level, advances in high-throughput genotyping technology have resolved several gradients which define different geographical areas with good precision. When Northern and Southern European groups were considered separately, there were clear genetic distinctions. Intra-country genetic differences were also evident, especially in Finland and, to a lesser extent, within other European populations. Here, we present the first analysis using the 125,799 genome-wide Single Nucleotide Polymorphisms (SNPs) data of 1,014 Italians with wide geographical coverage. We showed by using Principal Component analysis and model-based individual ancestry analysis, that the current population of Sardinia can be clearly differentiated genetically from mainland Italy and Sicily, and that a certain degree of genetic differentiation is detectable within the current Italian peninsula population. Pair-wise FST statistics Northern and Southern Italy

In spite of the common belief of Europe as reasonably homogeneous at genetic level, advances in high-throughput genotyping technology have resolved several gradients which define different geographical areas with good precision. When Northern and Southern European groups were considered separately, there were clear genetic distinctions. Intra-country genetic differences were also evident, especially in Finland and, to a lesser extent, within other European populations. Here, we present the first analysis using the 125,799 genome-wide Single Nucleotide Polymorphisms (SNPs) data of 1,014 Italians with wide geographical coverage. We showed by using Principal Component analysis and model-based individual ancestry analysis, that the current population of Sardinia can be clearly differentiated genetically from mainland Italy and Sicily, and that a certain degree of genetic differentiation is detectable within the current Italian peninsula population. Pair-wise FST statistics Northern and Southern Italy

We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P , 10 -4 for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10 -8 to P = 1.9 × 10 -11). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10 -4), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased ...

Single Nucleotide Polymorphism of ADIPOQ Gene (Rs822393) Is Associated with Lipid Profile, Adiponectin Levels and Ratio of Adiponectin/Leptin ratio in Adult Obese Subjects. PubMed, SCI, Scopus, ESCI, PMC indexed

Asthma is a chronic respiratory disease whose genetic basis has been explored for over two decades, most recently via genome-wide association studies. We sought to find asthma-susceptibility variants by using probands from a single population in both family-based and case-control association designs. We used probands from the Childhood Asthma Management Program (CAMP) in two primary genome-wide association study designs: (1) probands were combined with publicly available population controls in a case-control design, and (2) probands and their parents were used in a family-based design. We followed a two-stage replication process utilizing three independent populations to validate our primary findings. We found that single nucleotide polymorphisms with similar case-control and family-based association results were more likely to replicate in the independent populations, than those with the smallest p-values in either the case-control or family-based design alone. The single nucleotide polymorphism that

We describe here a system for the rapid identification, assay development, and characterization of gene-based single nucleotide polymorphisms (SNPs). This system couples informatics tools that mine candidate SNPs from public expressed sequence tag resources and automatically designs assay reagents with detection by a chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry platform. As a proof of concept of this system, a genomewide collection of reagents for 9,115 gene-based SNP genetic markers was rapidly developed and validated. These data provide preliminary insights into patterns of polymorphism in a genomewide collection of gene-based polymorphisms.. ...

Among the 66 patients, 60 received gefitinib (Group A) and 27 received erlotinib (Group B). 21 were treated with both gefitinib and erlotinib at different times. Severe hepatotoxicity was detected in 19 (32%) from Group A and 6 (22%) from Group B. Poor metabolizer (PM) was defined as homozygous of variant allele (SNPs) which reduced metabolic enzyme activity. The phenotypes were as follows: CYP3A5, PM/ non-PM = 34/ 32; CYP2D6, PM/ non-PM = 5/ 61; and VKORC1, PM/ non-PM = 55/ 11. In Group A, severe hepatotoxicity rate was significantly higher among patients with PM for CYP3A5 (PM vs. non-PM: 48% vs. 14%; p < 0.01), PM for CYP2D6 (PM vs. non-PM: 80% vs. 27%; p = 0.04) and non-PM for VKORC1 (PM vs. non-PM: 26% vs. 67%; p = 0.02). In Group B, any types of SNPs were not correlated with severe hepatotoxicity rate. Among 8 patients whose treatments were changed from gefitinib to erlotinib because of severe hepatotoxicity at the initial EGFR-TKI treatment, 7 patients exhibited an improvement of ...

We used Sequenom® MassARRAY® and iPLEX™ Gold genotyping assay to develop a multiplexed variety identification assay for the Australian barley industry. Correct identification and traceability of barley varieties is a prominent issue for quality assurance throughout the entire barley production supply chain in Australia and worldwide. Malting characteristics are variety dependent thus sourcing approved varieties which are uncontaminated with other malting or feed varieties is vital to product consistency. Fast, robust variety identification requires a stable marker that is not influenced by environment, and a platform which is capable of high throughput genotyping. In order to facilitate rapid, high throughput identification of barley varieties, we have developed a multiplexed SNP genotyping assay capable of determining the identity of each of 60 Australian barley varieties with precision and speed. Sequenom® MassARRAY® and iPLEX™ Gold genotyping was precise and a unique SNP barcode of up to 20