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Generalized T2 Test for Genome Association Studies

Xiong, Momiao; Zhao, Jinying; Boerwinkle, Eric
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.37%
Recent progress in the development of single-nucleotide polymorphism (SNP) maps within genes and across the genome provides a valuable tool for fine-mapping and has led to the suggestion of genomewide association studies to search for susceptibility loci for complex traits. Test statistics for genome association studies that consider a single marker at a time, ignoring the linkage disequilibrium between markers, are inefficient. In this study, we present a generalized T2 statistic for association studies of complex traits, which can utilize multiple SNP markers simultaneously and considers the effects of multiple disease-susceptibility loci. This generalized T2 statistic is a corollary to that originally developed for multivariate analysis and has a close relationship to discriminant analysis and common measure of genetic distance. We evaluate the power of the generalized T2 statistic and show that power to be greater than or equal to those of the traditional χ2 test of association and a similar haplotype-test statistic. Finally, examples are given to evaluate the performance of the proposed T2 statistic for association studies using simulated and real data.

Evidence for Linkage and Association with Reading Disability, on 6p21.3-22

Kaplan, D. E.; Gayán, J.; Ahn, J.; Won, T.-W.; Pauls, D.; Olson, R. K.; DeFries, J. C.; Wood, F.; Pennington, B. F.; Page, G. P.; Smith, S. D.; Gruen, J. R.
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.35%
Reading disability (RD), or dyslexia, is a common heterogeneous syndrome with a large genetic component. Several studies have consistently found evidence for a quantitative-trait locus (QTL) within the 17 Mb (14.9 cM) that span D6S109 and D6S291 on chromosome 6p21.3-22. To characterize further linkage to the QTL, to define more accurately the location and the effect size, and to identify a peak of association, we performed Haseman-Elston and DeFries-Fulker linkage analyses, as well as transmission/disequilibrium, total-association, and variance-components analyses, on 11 quantitative reading and language phenotypes. One hundred four families with RD were genotyped with a new panel of 29 markers that spans 9 Mb of this region. Linkage results varied widely in degree of statistical significance for the different linkage tests, but multipoint analysis suggested a peak near D6S461. The average 6p QTL heritability for the 11 reading and language phenotypes was 0.27, with a maximum of 0.66 for orthographic choice. Consistent with the region of linkage described by these studies and others, there was a peak of transmission disequilibrium with a QTL centered at JA04 (χ2=9.48; empirical P=.0033; orthographic choice), and there was strong evidence for total association at this same marker (χ2=11.49; P=.0007; orthographic choice). Although the boundaries of the peak could not be precisely defined...

Accounting for Linkage in Family-Based Tests of Association with Missing Parental Genotypes

Martin, Eden R.; Bass, Meredyth P.; Hauser, Elizabeth R.; Kaplan, Norman L.
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.37%
In studies of complex diseases, a common paradigm is to conduct association analysis at markers in regions identified by linkage analysis, to attempt to narrow the region of interest. Family-based tests for association based on parental transmissions to affected offspring are often used in fine-mapping studies. However, for diseases with late onset, parental genotypes are often missing. Without parental genotypes, family-based tests either compare allele frequencies in affected individuals with those in their unaffected siblings or use siblings to infer missing parental genotypes. An example of the latter approach is the score test implemented in the computer program TRANSMIT. The inference of missing parental genotypes in TRANSMIT assumes that transmissions from parents to affected siblings are independent, which is appropriate when there is no linkage. However, using computer simulations, we show that, when the marker and disease locus are linked and the data set consists of families with multiple affected siblings, this assumption leads to a bias in the score statistic under the null hypothesis of no association between the marker and disease alleles. This bias leads to an inflated type I error rate for the score test in regions of linkage. We present a novel test for association in the presence of linkage (APL) that correctly infers missing parental genotypes in regions of linkage by estimating identity-by-descent parameters...

Selection and Evaluation of Tagging SNPs in the Neuronal-Sodium-Channel Gene SCN1A: Implications for Linkage-Disequilibrium Gene Mapping

Weale, Mike E.; Depondt, Chantal; Macdonald, Stuart J.; Smith, Alice; Lai, Poh San; Shorvon, Simon D.; Wood, Nicholas W.; Goldstein, David B.
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.34%
Association studies are widely seen as the most promising approach for finding polymorphisms that influence genetically complex traits, such as common diseases and responses to their treatment. Considerable interest has therefore recently focused on the development of methods that efficiently screen genomic regions or whole genomes for gene variants associated with complex phenotypes. One key element in this search is the use of linkage disequilibrium to gain maximal information from typing a selected subset of highly informative single-nucleotide polymorphism (SNP) markers, now often called “tagging SNPs” (tSNPs). Probably the most common approach to linkage-disequilibrium gene mapping involves a three-step program: (1) characterization of the haplotype structure in candidate genes or genomic regions of interest, (2) identification of tSNPs sufficient to represent the most common haplotypes, and (3) typing of tSNPs in clinical material. Early definitions of tSNPs focused on the amount of haplotype diversity that they explained. To select tSNPs that would have maximal power in a genetic association study, however, we have developed optimization criteria based on the r2 measure of association and have compared these with other criteria based on the haplotype diversity. To evaluate the full program and to assess how well the selected tags are likely to perform...

Selecting a Maximally Informative Set of Single-Nucleotide Polymorphisms for Association Analyses Using Linkage Disequilibrium

Carlson, Christopher S.; Eberle, Michael A.; Rieder, Mark J.; Yi, Qian; Kruglyak, Leonid; Nickerson, Deborah A.
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.34%
Common genetic polymorphisms may explain a portion of the heritable risk for common diseases. Within candidate genes, the number of common polymorphisms is finite, but direct assay of all existing common polymorphism is inefficient, because genotypes at many of these sites are strongly correlated. Thus, it is not necessary to assay all common variants if the patterns of allelic association between common variants can be described. We have developed an algorithm to select the maximally informative set of common single-nucleotide polymorphisms (tagSNPs) to assay in candidate-gene association studies, such that all known common polymorphisms either are directly assayed or exceed a threshold level of association with a tagSNP. The algorithm is based on the r2 linkage disequilibrium (LD) statistic, because r2 is directly related to statistical power to detect disease associations with unassayed sites. We show that, at a relatively stringent r2 threshold (r2>0.8), the LD-selected tagSNPs resolve >80% of all haplotypes across a set of 100 candidate genes, regardless of recombination, and tag specific haplotypes and clades of related haplotypes in nonrecombinant regions. Thus, if the patterns of common variation are described for a candidate gene...

Matching Strategies for Genetic Association Studies in Structured Populations

Hinds, David A.; Stokowski, Renee P.; Patil, Nila; Konvicka, Karel; Kershenobich, David; Cox, David R.; Ballinger, Dennis G.
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.35%
Association studies in populations that are genetically heterogeneous can yield large numbers of spurious associations if population subgroups are unequally represented among cases and controls. This problem is particularly acute for studies involving pooled genotyping of very large numbers of single-nucleotide–polymorphism (SNP) markers, because most methods for analysis of association in structured populations require individual genotyping data. In this study, we present several strategies for matching case and control pools to have similar genetic compositions, based on ancestry information inferred from genotype data for ∼300 SNPs tiled on an oligonucleotide-based genotyping array. We also discuss methods for measuring the impact of population stratification on an association study. Results for an admixed population and a phenotype strongly confounded with ancestry show that these simple matching strategies can effectively mitigate the impact of population stratification.

Joint Modeling of Linkage and Association: Identifying SNPs Responsible for a Linkage Signal

Li, Mingyao; Boehnke, Michael; Abecasis, Gonçalo R.
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.37%
Once genetic linkage has been identified for a complex disease, the next step is often association analysis, in which single-nucleotide polymorphisms (SNPs) within the linkage region are genotyped and tested for association with the disease. If a SNP shows evidence of association, it is useful to know whether the linkage result can be explained, in part or in full, by the candidate SNP. We propose a novel approach that quantifies the degree of linkage disequilibrium (LD) between the candidate SNP and the putative disease locus through joint modeling of linkage and association. We describe a simple likelihood of the marker data conditional on the trait data for a sample of affected sib pairs, with disease penetrances and disease-SNP haplotype frequencies as parameters. We estimate model parameters by maximum likelihood and propose two likelihood-ratio tests to characterize the relationship of the candidate SNP and the disease locus. The first test assesses whether the candidate SNP and the disease locus are in linkage equilibrium so that the SNP plays no causal role in the linkage signal. The second test assesses whether the candidate SNP and the disease locus are in complete LD so that the SNP or a marker in complete LD with it may account fully for the linkage signal. Our method also yields a genetic model that includes parameter estimates for disease-SNP haplotype frequencies and the degree of disease-SNP LD. Our method provides a new tool for detecting linkage and association and can be extended to study designs that include unaffected family members.

The Genetic Dissection of Complex Traits in a Founder Population

Ober, Carole; Abney, Mark; McPeek, Mary Sara
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.36%
We estimated broad heritabilities (H2) and narrow heritabilities (h2) and conducted genomewide screens, using a novel association-based mapping approach for 20 quantitative trait loci (QTLs) among the Hutterites, a founder population that practices a communal lifestyle. Heritability estimates ranged from .21 for diastolic blood pressure (DBP) to .99 for whole-blood serotonin levels. Using a multipoint method to detect association under a recessive model we found evidence of major QTLs for six traits: low-density lipoprotein (LDL), triglycerides, lipoprotein (a) (Lp[a]), systolic blood pressure (SBP), serum cortisol, and whole-blood serotonin. Second major QTLs for Lp(a) and for cortisol were identified using a single-point method to detect association under a general two-allele model. The heritabilities for these six traits ranged from .37 for triglycerides to .99 for serotonin, and three traits (LDL, SBP, and serotonin) had significant dominance variances (i.e., H2 > h2). Surprisingly, there was little correlation between measures of heritability and the strength of association on a genomewide screen (P>.50), suggesting that heritability estimates per se do not identify phenotypes that are influenced by genes with major effects. The present study demonstrates the feasibility of genomewide association studies for QTL mapping. However...

Bipolar I Disorder and Schizophrenia: A 440–Single-Nucleotide Polymorphism Screen of 64 Candidate Genes among Ashkenazi Jewish Case-Parent Trios

Fallin, M. Daniele ; Lasseter, Virginia K. ; Avramopoulos, Dimitrios ; Nicodemus, Kristin K. ; Wolyniec, Paula S. ; McGrath, John A. ; Steel, Gary ; Nestadt, Gerald ; Liang, Kung-Yee ; Huganir, Richard L. ; Valle, David ; Pulver, Ann E.
Fonte: American Society of Human Genetics Publicador: American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.36%
Bipolar, schizophrenia, and schizoaffective disorders are common, highly heritable psychiatric disorders, for which familial coaggregation, as well as epidemiological and genetic evidence, suggests overlapping etiologies. No definitive susceptibility genes have yet been identified for any of these disorders. Genetic heterogeneity, combined with phenotypic imprecision and poor marker coverage, has contributed to the difficulty in defining risk variants. We focused on families of Ashkenazi Jewish descent, to reduce genetic heterogeneity, and, as a precursor to genomewide association studies, we undertook a single-nucleotide polymorphism (SNP) genotyping screen of 64 candidate genes (440 SNPs) chosen on the basis of previous linkage or of association and/or biological relevance. We genotyped an average of 6.9 SNPs per gene, with an average density of 1 SNP per 11.9 kb in 323 bipolar I disorder and 274 schizophrenia or schizoaffective Ashkenazi case-parent trios. Using single-SNP and haplotype-based transmission/disequilibrium tests, we ranked genes on the basis of strength of association (P<.01). Six genes (DAO, GRM3, GRM4, GRIN2B, IL2RB, and TUBA8) met this criterion for bipolar I disorder; only DAO has been previously associated with bipolar disorder. Six genes (RGS4...

Association Mapping in Structured Populations

Pritchard, Jonathan K.; Stephens, Matthew; Rosenberg, Noah A.; Donnelly, Peter
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.36%
The use, in association studies, of the forthcoming dense genomewide collection of single-nucleotide polymorphisms (SNPs) has been heralded as a potential breakthrough in the study of the genetic basis of common complex disorders. A serious problem with association mapping is that population structure can lead to spurious associations between a candidate marker and a phenotype. One common solution has been to abandon case-control studies in favor of family-based tests of association, such as the transmission/disequilibrium test (TDT), but this comes at a considerable cost in the need to collect DNA from close relatives of affected individuals. In this article we describe a novel, statistically valid, method for case-control association studies in structured populations. Our method uses a set of unlinked genetic markers to infer details of population structure, and to estimate the ancestry of sampled individuals, before using this information to test for associations within subpopulations. It provides power comparable with the TDT in many settings and may substantially outperform it if there are conflicting associations in different subpopulations.

SNPing Away at Complex Diseases: Analysis of Single-Nucleotide Polymorphisms around APOE in Alzheimer Disease

Martin, Eden R.; Lai, Eric H.; Gilbert, John R.; Rogala, Allison R.; Afshari, A. J.; Riley, John; Finch, K. L.; Stevens, J. F.; Livak, K. J.; Slotterbeck, Brandon D.; Slifer, Susan H.; Warren, Liling L.; Conneally, P. Michael; Schmechel, Donald E.; Purvis
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.37%
There has been great interest in the prospects of using single-nucleotide polymorphisms (SNPs) in the search for complex disease genes, and several initiatives devoted to the identification and mapping of SNPs throughout the human genome are currently underway. However, actual data investigating the use of SNPs for identification of complex disease genes are scarce. To begin to look at issues surrounding the use of SNPs in complex disease studies, we have initiated a collaborative SNP mapping study around APOE, the well-established susceptibility gene for late-onset Alzheimer disease (AD). Sixty SNPs in a 1.5-Mb region surrounding APOE were genotyped in samples of unrelated cases of AD, in controls, and in families with AD. Standard tests were conducted to look for association of SNP alleles with AD, in cases and controls. We also used family-based association analyses, including recently developed methods to look for haplotype association. Evidence of association (P⩽.05) was identified for 7 of 13 SNPs, including the APOE-4 polymorphism, spanning 40 kb on either side of APOE. As expected, very strong evidence for association with AD was seen for the APOE-4 polymorphism, as well as for two other SNPs that lie <16 kb from APOE. Haplotype analysis using family data increased significance over that seen in single-locus tests for some of the markers...

Family-Based Tests of Association in the Presence of Linkage

Lake, Stephen L.; Blacker, Deborah; Laird, Nan M.
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
65.38%
Linkage analysis may not provide the necessary resolution for identification of the genes underlying phenotypic variation. This is especially true for gene-mapping studies that focus on complex diseases that do not exhibit Mendelian inheritance patterns. One positional genomic strategy involves application of association methodology to areas of identified linkage. Detection of association in the presence of linkage localizes the gene(s) of interest to more-refined regions in the genome than is possible through linkage analysis alone. This strategy introduces a statistical complexity when family-based association tests are used: the marker genotypes among siblings are correlated in linked regions. Ignoring this correlation will compromise the size of the statistical hypothesis test, thus clouding the interpretation of test results. We present a method for computing the expectation of a wide range of association test statistics under the null hypothesis that there is linkage but no association. To standardize the test statistic, an empirical variance-covariance estimator that is robust to the sibling marker-genotype correlation is used. This method is widely applicable: any type of phenotypic measure or family configuration can be used. For example...

Family-Based Tests of Association and Linkage That Use Unaffected Sibs, Covariates, and Interactions

Lunetta, Kathryn L.; Faraone, Stephen V.; Biederman, Joseph; Laird, Nan M.
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
65.36%
We extend the methodology for family-based tests of association and linkage to allow for both variation in the phenotypes of subjects and incorporation of covariates into general-score tests of association. We use standard association models for a phenotype and any number of predictors. We then construct a score statistic, using likelihoods for the distribution of phenotype, given genotype. The distribution of the score is computed as a function of offspring genotypes, conditional on parental genotypes and trait values for offspring and parents. This approach provides a natural extension of the transmission/disequilibrium test to any phenotype and to multiple genes or environmental factors and allows the study of gene-gene and gene-environment interaction. When the trait varies among subjects or when covariates are included in the association model, the score statistic depends on one or more nuisance parameters. We suggest two approaches for obtaining parameter estimates: (1) choosing the estimate that minimizes the variance of the test statistic and (2) maximizing the statistic over a nuisance parameter and using a corrected P value. We apply our methods to a sample of families with attention-deficit/hyperactivity disorder and provide examples of how covariates and gene-environment and gene-gene interactions can be incorporated.

Fine-mapping of colorectal cancer susceptibility loci at 8q23.3, 16q22.1 and 19q13.11: refinement of association signals and use of in silico analysis to suggest functional variation and unexpected candidate target genes

Carvajal-Carmona, Luis G.; Cazier, Jean-Baptiste; Jones, Angela M.; Howarth, Kimberley; Broderick, Peter; Pittman, Alan; Dobbins, Sara; Tenesa, Albert; Farrington, Susan; Prendergast, James; Theodoratou, Evi; Barnetson, Rebecca; Conti, David; Newcomb, Pol
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.36%
We have previously identified several colorectal cancer (CRC)-associated polymorphisms using genome-wide association (GWA) analysis. We sought to fine-map the location of the functional variants for three of these regions at 8q23.3 (EIF3H), 16q22.1 (CDH1/CDH3) and 19q13.11 (RHPN2). We genotyped two case–control sets at high density in the selected regions and used existing data from four other case–control sets, comprising a total of 9328 CRC cases and 10 480 controls. To improve marker density, we imputed genotypes from the 1000 Genomes Project and Hapmap3 data sets. All three regions contained smaller areas in which a cluster of single nucleotide polymorphisms (SNPs) showed clearly stronger association signals than surrounding SNPs, allowing us to assign those areas as the most likely location of the disease-associated functional variant. Further fine-mapping within those areas was generally unhelpful in identifying the functional variation based on strengths of association. However, functional annotation suggested a relatively small number of functional SNPs, including some with potential regulatory function at 8q23.3 and 16q22.1 and a non-synonymous SNP in RPHN2. Interestingly, the expression quantitative trait locus browser showed a number of highly associated SNP alleles correlated with mRNA expression levels not of EIF3H and CDH1 or CDH3...

Allelic heterogeneity and more detailed analyses of known loci explain additional phenotypic variation and reveal complex patterns of association

Wood, Andrew R.; Hernandez, Dena G.; Nalls, Michael A.; Yaghootkar, Hanieh; Gibbs, J. Raphael; Harries, Lorna W.; Chong, Sean; Moore, Matthew; Weedon, Michael N.; Guralnik, Jack M.; Bandinelli, Stefania; Murray, Anna; Ferrucci, Luigi; Singleton, Andrew B;
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.36%
The identification of multiple signals at individual loci could explain additional phenotypic variance (‘missing heritability’) of common traits, and help identify causal genes. We examined gene expression levels as a model trait because of the large number of strong genetic effects acting in cis. Using expression profiles from 613 individuals, we performed genome-wide single nucleotide polymorphism (SNP) analyses to identify cis-expression quantitative trait loci (eQTLs), and conditional analysis to identify second signals. We examined patterns of association when accounting for multiple SNPs at a locus and when including additional SNPs from the 1000 Genomes Project. We identified 1298 cis-eQTLs at an approximate false discovery rate 0.01, of which 118 (9%) showed evidence of a second independent signal. For this subset of 118 traits, accounting for two signals resulted in an average 31% increase in phenotypic variance explained (Wilcoxon P< 0.0001). The association of SNPs with cis gene expression could increase, stay similar or decrease in significance when accounting for linkage disequilibrium with second signals at the same locus. Pairs of SNPs increasing in significance tended to have gene expression increasing alleles on opposite haplotypes...

Association of Polymorphisms in the Hepatocyte Growth Factor Gene Promoter with Keratoconus

Burdon, Kathryn P.; Macgregor, Stuart; Bykhovskaya, Yelena; Javadiyan, Sharhbanou; Li, Xiaohui; Laurie, Kate J.; Muszynska, Dorota; Lindsay, Richard; Lechner, Judith; Haritunians, Talin; Henders, Anjali K.; Dash, Durga; Siscovick, David; Anand, Seema; Ald
Fonte: Association for Research in Vision and Ophthalmology, Inc. Publicador: Association for Research in Vision and Ophthalmology, Inc.
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.35%
This is a meta-analysis of two genome-wide association studies that found evidence of association of keratoconus with polymorphisms in the promoter of the HGF gene. One polymorphism is associated with higher levels of serum HGF.

Association between Myopia and Glaucoma in the United States Population

Qiu, Mary; Wang, Sophia Y.; Singh, Kuldev; Lin, Shan C.
Fonte: The Association for Research in Vision and Ophthalmology Publicador: The Association for Research in Vision and Ophthalmology
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.36%
This study found an association between myopia and visual field defects, which may represent an increased risk of glaucoma among myopes, and the lack of association between myopia and self-reported glaucoma may suggest a need for greater glaucoma surveillance in this population.

Nursing Routine Data as a Basis for Association Analysis in the Domain of Nursing Knowledge

Sellemann, Björn; Stausberg, Jürgen; Hübner, Ursula
Fonte: American Medical Informatics Association Publicador: American Medical Informatics Association
Tipo: Artigo de Revista Científica
Publicado em 23/06/2012 EN
Relevância na Pesquisa
55.37%
This paper describes the data mining method of association analysis within the framework of Knowledge Discovery in Databases (KDD) with the aim to identify standard patterns of nursing care. The approach is application-oriented and used on nursing routine data of the method LEP nursing 2. The increasing use of information technology in hospitals, especially of nursing information systems, requires the storage of large data sets, which hitherto have not always been analyzed adequately. Three association analyses for the days of admission, surgery and discharge, have been performed. The results of almost 1.5 million generated association rules indicate that it is valid to apply association analysis to nursing routine data. All rules are semantically trivial, since they reflect existing knowledge from the domain of nursing. This may be due either to the method LEP Nursing 2, or to the nursing activities themselves. Nonetheless, association analysis may in future become a useful analytical tool on the basis of structured nursing routine data.

Lack of association between LEPR Lys656Asn or Ser343Ser polymorphisms and cancer susceptibility: A meta-analysis

LIU, PENG-CHENG; YANG, YUN-JI; LIU, RUN; HUANG, CHANG-JIA; SHU, HE-XI; GONG, JIN-PENG; CHEN, QUAN-CHI; YANG, YONG; CAI, MING
Fonte: D.A. Spandidos Publicador: D.A. Spandidos
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.37%
Previous studies have shown conflicting results between the association of leptin receptor (LEPR) genetic polymorphisms and cancer risk. The frequent LEPR Lys656Asn or Ser343Ser genetic polymorphism has been demonstrated to be functional and may promote genetic susceptibility to cancers. However, the association between the LEPR Lys656Asn or Ser343Ser genetic polymorphism and cancer risk remains to be determined. To improve the understanding of the LEPR Lys656Asn or Ser343Ser genetic polymorphism role in global cancer, a comprehensive meta-analysis was conducted that comprised 2,480 cases and 3,162 controls. The LEPR Lys656Asn or Ser343Ser genetic polymorphism did not significantly affect the cancer risk. In the stratified analysis, there was no significant association of the LEPR Lys656Asn or Ser343Ser variants with any type of cancer under any model. In addition, significantly increased risks were found in the Asian population in heterozygous codominant [odds ratio (OR), 1.24 (1.01–1.53)] and dominant [OR, 1.24 (1.02–1.50)] genetic models. A significantly increased susceptibility to cancer was not found when stratified by study design. There were no significant differences found in genotype method and sample size in cases among the genotypes. These findings indicated a lack of association between LEPR Lys656Asn or Ser343Ser polymorphisms and cancer susceptibility...

Candidate-Gene Screening and Association Analysis at the Autism-Susceptibility Locus on Chromosome 16p: Evidence of Association at GRIN2A and ABAT

Barnby, Gabrielle; Abbott, Aaron; Sykes, Nuala; Morris, Andrew; Weeks, Daniel E.; Mott, Richard; Lamb, Janine; Bailey, Anthony J.; Monaco, Anthony P.;
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.37%
Autism is a highly heritable neurodevelopmental disorder whose underlying genetic causes have yet to be identified. To date, there have been eight genome screens for autism, two of which identified a putative susceptibility locus on chromosome 16p. In the present study, 10 positional candidate genes that map to 16p11-13 were examined for coding variants: A2BP1, ABAT, BFAR, CREBBP, EMP2, GRIN2A, MRTF-B, SSTR5, TBX6, and UBN1. Screening of all coding and regulatory regions by denaturing high-performance liquid chromatography identified seven nonsynonymous changes. Five of these mutations were found to cosegregate with autism, but the mutations are not predicted to have deleterious effects on protein structure and are unlikely to represent significant etiological variants. Selected variants from candidate genes were genotyped in the entire International Molecular Genetics Study of Autism Consortium collection of 239 multiplex families and were tested for association with autism by use of the pedigree disequilibrium test. Additionally, genotype frequencies were compared between 239 unrelated affected individuals and 192 controls. Patterns of linkage disequilibrium were investigated, and the transmission of haplotypes across candidate genes was tested for association. Evidence of single-marker association was found for variants in ABAT...