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Individual SNPs (individual + snp)
Selected AbstractsGENETIC STUDY: FULL ARTICLE: Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genesADDICTION BIOLOGY, Issue 3 2010Richard A. Grucza ABSTRACT Nicotine dependence is moderately heritable, but identified genetic associations explain only modest portions of this heritability. We analyzed 3369 SNPs from 349 candidate genes and investigated whether incorporation of SNP-by-environment interaction into association analyses might bolster gene discovery efforts and prediction of nicotine dependence. Specifically, we incorporated the interaction between allele count and age at onset of regular smoking (AOS) into association analyses of nicotine dependence. Subjects were from the Collaborative Genetic Study of Nicotine Dependence and included 797 cases ascertained for Fagerström nicotine dependence and 811 non-nicotine-dependent smokers as controls, all of European descent. Compared with main effect models, SNP × AOS interaction models resulted in higher numbers of nominally significant tests, increased predictive utility at individual SNPs and higher predictive utility in a multi-locus model. Some SNPs previously documented in main effect analyses exhibited improved fits in the joint analysis, including rs16969968 from CHRNA5 and rs2314379 from MAP3K4. CHRNA5 exhibited larger effects in later-onset smokers, in contrast with a previous report that suggested the opposite interaction (Weiss et al. 2008). However, a number of SNPs that did not emerge in main effect analyses were among the strongest findings in the interaction analyses. These include SNPs located in GRIN2B (P = 1.5 × 10,5), which encodes a subunit of the N-methyl-D-aspartate receptor channel, a key molecule in mediating age-dependent synaptic plasticity. Incorporation of logically chosen interaction parameters, such as AOS, into genetic models of substance use disorders may increase the degree of explained phenotypic variation and constitutes a promising avenue for gene discovery. [source] Association tests using kernel-based measures of multi-locus genotype similarity between individualsGENETIC EPIDEMIOLOGY, Issue 3 2010Indranil Mukhopadhyay Abstract In a genetic association study, it is often desirable to perform an overall test of whether any or all single-nucleotide polymorphisms (SNPs) in a gene are associated with a phenotype. Several such tests exist, but most of them are powerful only under very specific assumptions about the genetic effects of the individual SNPs. In addition, some of the existing tests assume that the direction of the effect of each SNP is known, which is a highly unlikely scenario. Here, we propose a new kernel-based association test of joint association of several SNPs. Our test is non-parametric and robust, and does not make any assumption about the directions of individual SNP effects. It can be used to test multiple correlated SNPs within a gene and can also be used to test independent SNPs or genes in a biological pathway. Our test uses an analysis of variance paradigm to compare variation between cases and controls to the variation within the groups. The variation is measured using kernel functions for each marker, and then a composite statistic is constructed to combine the markers into a single test. We present simulation results comparing our statistic to the U -statistic-based method by Schaid et al. ([2005] Am. J. Hum. Genet. 76:780,793) and another statistic by Wessel and Schork ([2006] Am. J. Hum. Genet. 79:792,806). We consider a variety of different disease models and assumptions about how many SNPs within the gene are actually associated with disease. Our results indicate that our statistic has higher power than other statistics under most realistic conditions. Genet. Epidemiol. 34: 213,221, 2010. © 2009 Wiley-Liss, Inc. [source] Differential parental transmission of markers in RUNX2 among cleft case-parent trios from four populationsGENETIC EPIDEMIOLOGY, Issue 6 2008Jae Woong Sull Abstract Isolated cleft lip with or without cleft palate (CL/P) is among the most common human birth defects, with a prevalence around 1 in 700 live births. The Runt-related transcription factor 2 (RUNX2) gene has been suggested as a candidate gene for CL/P based largely on mouse models; however, no human studies have focused on RUNX2 as a risk factor for CL/P. This study examines the association between markers in RUNX2 and isolated, nonsyndromic CL/P using a case-parent trio design, while considering parent-of-origin effects. Case-parent trios from four populations (77 from Maryland, 146 from Taiwan, 35 from Singapore, and 40 from Korea) were genotyped for 24 single nucleotide polymorphisms (SNPs) in the RUNX2 gene. We performed the transmission disequilibrium test on individual SNPs. Parent-of-origin effects were assessed using the transmission asymmetry test and the parent-of-origin likelihood ratio test (PO-LRT). When all trios were combined, the transmission asymmetry test revealed a block of 11 SNPs showing excess maternal transmission significant at the P<0.01 level, plus one SNP (rs1934328) showing excess paternal transmission (P=0.002). For the 11 SNPs showing excess maternal transmission, odds ratios of being transmitted to the case from the mother ranged between 3.00 and 4.00. The parent-of-origin likelihood ratio tests for equality of maternal and paternal transmission were significant for three individual SNPs (rs910586, rs2819861, and rs1934328). Thus, RUNX2 appears to influence risk of CL/P through a parent-of-origin effect with excess maternal transmission. Genet. Epidemiol. 2008. © 2008 Wiley-Liss, Inc. [source] Evolutionary-based grouping of haplotypes in association analysisGENETIC EPIDEMIOLOGY, Issue 3 2005Jung-Ying Tzeng Abstract Haplotypes incorporate more information about the underlying polymorphisms than do genotypes for individual SNPs, and are considered as a more informative format of data in association analysis. To model haplotypes requires high degrees of freedom, which could decrease power and limit a model's capacity to incorporate other complex effects, such as gene-gene interactions. Even within haplotype blocks, high degrees of freedom are still a concern unless one chooses to discard rare haplotypes. To increase the efficiency and power of haplotype analysis, we adapt the evolutionary concepts of cladistic analyses and propose a grouping algorithm to cluster rare haplotypes to the corresponding ancestral haplotypes. The algorithm determines the cluster bases by preserving common haplotypes using a criterion built on the Shannon information content. Each haplotype is then assigned to its appropriate clusters probabilistically according to the cladistic relationship. Through this algorithm, we perform association analysis based on groups of haplotypes. Simulation results indicate power increases for performing tests on the haplotype clusters when compared to tests using original haplotypes or the truncated haplotype distribution. Genet. Epidemiol. © 2005 Wiley-Liss, Inc. [source] Genotypes of varicella-zoster virus wild-type strains in GermanyJOURNAL OF MEDICAL VIROLOGY, Issue 6 2008A. Sauerbrei Abstract Surveillance of varicella-zoster virus (VZV) genotypes is indicated in Germany after implementation of universal varicella vaccination. This article reports genotyping data of 77 VZV strains obtained from 54 patients with varicella, 1 newborn with congenital varicella syndrome, 2 fetuses with intrauterine VZV infection and 20 cases with zoster. Fragments of the open reading frames (ORF) 1, 21, 22, 37, 50, 54, and 60 were analyzed by sequencing. In addition, the PstI polymorphism of the ORF 38 was characterized. Thirty strains, 22 from varicella and 8 from zoster, had the genetic markers of genotype E2, 2 of them carried new single nucleotide polymorphisms (SNP). Twenty-nine VZV isolates, 17 from varicella, and 12 from zoster, could be analyzed as E1 strains, 6 of them as E1 variants containing individual SNPs. Finally, 17 strains taken from primary VZV infection were classified as genotype M1, 13 of which belonged to the M1 subtype 1, 3 to the M1 subtype 2, and 1 to the M1 subtype 3. One strain was regarded as potential E2/J recombinant. In conclusion, VZV genotypes E2, E1, and M1 can be found in nearly equal incidence in varicella in Germany. The most frequent group is attributed to the genotype E2. Genotype M1 strains can only be detected after primary VZV infection and not in zoster cases. The possible recombinant could not be classified definitely by the scattered SNP method used and, therefore, has to be confirmed by full-genome sequencing studies. J. Med. Virol. 80:1123,1130, 2008. © 2008 Wiley-Liss, Inc. [source] Glutamate Decarboxylase Genes and Alcoholism in Han Taiwanese MenALCOHOLISM, Issue 11 2006El-Wui Loh Objective: Glutamate decarboxylase (GAD), the rate-limiting enzyme in the synthesis of , -aminobutyric acid (GABA), may be involved in the development of alcoholism. This study examined the possible roles of the genes that code for 2 forms of GAD (GAD1 and GAD2) in the development of alcoholism. Method: An association study was conducted among 140 male alcoholic subjects meeting the DSM-III-R criteria for alcohol dependence and 146 controls recruited from the Han Taiwanese in community and clinical settings. Psychiatric assessment of drinking conditions was conducted using a Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry. The SHEsis and Haploview programs were used in statistical analyses. Results: Nine single-nucleotide polymorphisms (SNPs) at the GAD1 gene were valid for further statistics. Between alcoholic subjects and controls, significant differences were found in genotype distributions of SNP1 (p=0.000), SNP2 (p=0.015), SNP4 (p=0.015), SNP5 (p=0.031), SNP6 (p=0.012), and SNP8 (p=0.004) and in allele distributions of SNP1 (p=0.001), SNP2 (p=0.009), and SNP8 (p=0.009). Permutation tests of SNP1, SNP2, and SNP8 demonstrated significant differences in allele frequencies but not in 2 major haplotype blocks. Three valid SNPs at the GAD2 gene demonstrated no associations with alcoholism. Further permutation tests in the only 1 haplotype block or individual SNPs demonstrated no significant differences. Conclusions: This is the first report indicating a possible significant role of the GAD1 gene in the development of alcohol dependence and/or the course of alcohol withdrawal and outcome of alcoholism. [source] Susceptibility loci reported in genome-wide association studies are associated with Crohn's disease in Canadian childrenALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 11 2010D. K. AMRE Aliment Pharmacol Ther,31, 1186,1191 Summary Background, Recent genome-wide association studies based on adult and paediatric populations have implicated >30 genes/loci as susceptibility loci for Crohn's disease (CD). Aims, To investigate whether reported genes/loci were also associated with CD in Canadian children. Design and Methods, A case-control design was implemented at three paediatric gastroenterology clinics in Canada. Children ,18 years of age with a confirmed diagnosis of CD were recruited along with controls. Single nucleotide polymorphisms (SNPs) in five genome-wide association studies reported genes/loci were genotyped. Associations between individual SNPs and CD were examined. Results, A total of 406 cases and 415 controls were studied. The mean (±s.d.) age of the cases was 12.3 (±3.2) years. Most cases were male (56.6%), had ileo-colonic disease (L3 ± L4, 52.0%) and inflammatory behaviour (B1 ± p, 86.9%) at diagnosis. Allelic association analysis (two-tailed) showed that three of the five targeted SNPs were significantly associated with overall susceptibility for CD (ZNF365, r10995271, P = 0.001; PTPN2, rs1893217, P = 0.005; STAT3, rs744166, P = 0.01). Associations with SNP rs4613763 in the PTGER4 locus were marginally nonsignificant (P = 0.07). The ZNF365 and STAT3 SNPs were predominantly associated with ileal disease with or without colonic involvement. Conclusion, The identified susceptibility genes/loci for adult-onset CD also confer risk for paediatric-onset CD. [source] A genome map of divergent artificial selection between Bos taurus dairy cattle and Bos taurus beef cattleANIMAL GENETICS, Issue 2 2009B. J. Hayes Summary A number of cattle breeds have become highly specialized for milk or beef production, following strong artificial selection for these traits. In this paper, we compare allele frequencies from 9323 single nucleotide polymorphism (SNP) markers genotyped in dairy and beef cattle breeds averaged in sliding windows across the genome, with the aim of identifying divergently selected regions of the genome between the production types. The value of the method for identifying selection signatures was validated by four sources of evidence. First, differences in allele frequencies between dairy and beef cattle at individual SNPs were correlated with the effects of those SNPs on production traits. Secondly, large differences in allele frequencies generally occurred in the same location for two independent data sets (correlation 0.45) between sliding window averages. Thirdly, the largest differences in sliding window average difference in allele frequencies were found on chromosome 20 in the region of the growth hormone receptor gene, which carries a mutation known to have an effect on milk production traits in a number of dairy populations. Finally, for the chromosome tested, the location of selection signatures between dairy and beef cattle was correlated with the location of selection signatures within dairy cattle. [source] Haplotypes Encompassing the KIAA0391 and PSMA6 Gene Cluster Confer a Genetic Link for Myocardial Infarction and Coronary Artery DiseaseANNALS OF HUMAN GENETICS, Issue 5 2009Osama Alsmadi Summary The role of the KIAA0391 and PSMA6 genes in predisposing individuals to disease is still not fully understood. We evaluated by molecular beacon-based genotyping assays the roles of five single nucleotide polymorphisms (SNPs) in the chromosomal region 14q13.2 harbouring the KIAA0391 and PSMA6 gene cluster in coronary artery disease (CAD) in the Saudi population. Two of the studied SNPs rs8008319 (denoted as 1) and rs7157492 (2), reside in the KIAA0391 locus, two others rs1048990 (3) and rs12878391 (4) are components of the PSMA6, while rs4981283 (5) resides downstream of both genes. In a study involving 1071 patients and 929 controls, none of the studied SNPs showed significant association with CAD. In contrast, two haplotypes consisting of 1A-2G-3C-4A-5A [O.R.(95% C.I.) = 1.49(0.95,2.35); p = 0.022] and 1A-2G-3G-4A-5A [2.24(0.84,5.98); p = 0.031] conferred risk for both CAD and myocardial infarction (MI) in a five-SNP locus model, while another comprising 1A-2G-3C-4A-5G [2.24(0.84,5.98); p = 0.079] showed a borderline association. One haplotype consisting of 1T-2G-3C-4G-5A [0.79(0.59,1.05); p = 0.015] exhibited protective properties and another, 1T-2G-3C-4A-5G [0.20(0.03,139); p = 0.073], showed a similar but weaker trend. Our study identified haplotypes in the chromosomal region encompassing the KIAA0391 and PSMA6 genes as a possible genetic link between CAD and MI. These results also suggest that haplotypes may be more informative than individual SNPs in identifying risk factors for disease. [source] Contribution of a haplotype in the HLA region to anti,cyclic citrullinated peptide antibody positivity in rheumatoid arthritis, independently of HLA,DRB1ARTHRITIS & RHEUMATISM, Issue 12 2009Yukinori Okada Objective To examine the risk of anti,cyclic citrullinated peptide (anti-CCP) antibody positivity in rheumatoid arthritis (RA) patients carrying certain haplotypes in the HLA region. Methods A total of 1,389 Japanese patients with RA were genotyped for 30 single-nucleotide polymorphisms (SNPs) in the HLA region using commercial oligonucleotide arrays (from Perlegen or Affymetrix) as well as for HLA,DRB1 alleles using a sequence-specific polymerase chain reaction method. Stepwise logistic regression was used to select from among the 30 SNPs the ones that represented a risk of anti-CCP antibody positivity. Haplotypes of the selected SNPs were inferred using an expectation-maximization algorithm. Associations of individual SNPs were evaluated with the Cochran-Armitage test for trend. DRB1 alleles and haplotypes were evaluated with the chi-square test. Heterogeneities of risks among the shared epitope (SE) and non-SE HLA,DRB1 alleles were examined using the exact test. Haplotype associations that were independent of individual HLA,DRB1 alleles were evaluated using the likelihood ratio test. Results Significant associations were found for 9 SNPs (smallest P value being 2.4 × 10,8) and in 4 HLA,DRB1 alleles (smallest P value being 2.0 × 10,10 in DRB1*0405). Stepwise logistic regression selected 4 SNPs (rs9262638, rs7775228, rs4713580, and rs9277359). Among the 16 inferred haplotypes of these 4 SNPs, 6 indicated significant associations (smallest P value being 1.9 × 10,11). Risks among SE and non-SE alleles were significantly heterogeneous (P = 0.0095 and P = 9.8 × 10,9, respectively), indicating the importance of stratification with individual DRB1 alleles rather than SE alleles. Conditional analysis of the risk associated with individual DRB1 alleles identified a risk haplotype that was independent of DRB1 (odds ratio 2.00 [95% confidence interval 1.44,2.79], P = 2.6 × 10,5). Conclusion Heterogeneous risks of anti-CCP antibody positivity were confirmed among SE and non-SE alleles in our patient population. A risk haplotype in the HLA region that is independent of HLA,DRB1 was confirmed. [source] | |||||||||||||