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Results for “Association analysis”

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PubMed2001

[Schizophrenia and dopamine D4 gene polymorphism in Chinese population: association analysis].

OBJECTIVE: To investigate the association of the 48 bp variable number tandem repeat (VNTR) polymorphism in the dopamine D4 receptor (DRD4) gene exon III with schizophrenia in Chinese Han population. METHODS: Case-control association study was adopted to analyze the association between the 48 bp VNTR polymorphism of DRD4 gene exon III in 510 DSM-IV schizophrenics and 171 psychiatrically normal controls. RESULTS: (1) The DRD4 gene 48 bp VNTR polymorphism was manifested as 2-7 repeats, with the 4 repeats the most common (78.6% in schizophrenics and 76.9% in controls respectively). The frequency of 2 repeats was 16.2% and 19.3% in the schizophrenics and controls respectively. (2) The genotypic frequency was statistically significantly different between the schizophrenics and the controls. The genotypic frequency of short tandem repeats (2/2 and 2/3 genotype) was lower in patients (3.3%) than in controls (10.5%) (chi 2 = 14.88, df = 2, P = 0.00). (3) the frequency of the genotype with 4-repeat allele in patients was higher (95.9%) than in controls (88.3%) (chi 2 = 13.00, df = 1, P = 0.000). CONCLUSION: The most common allele in Chinese schizophrenics was 4 repeats in the 48 bp VNTR polymorphism of DRD4 gene exon III. The repeat number of 48 bp is probably associated with schizophrenia. Lack of 2-3 repeats or excess of genotype with 4-repeat allele may be associated with increased vulnerability to schizophrenia.

Adult↗

PubMed2004

Cox proportional hazards survival regression in haplotype-based association analysis using the Stochastic-EM algorithm.

It is now widely recognized that haplotype information inferred from genotypes can be of great interest to better characterize the role of a candidate gene in the etiology of a complex trait in the context of association studies. Several works have recently advocated the simultaneous estimation of haplotype frequencies and haplotype effects in order to get a better efficiency in parameter estimation. Most of the available models can deal with a binary or a quantitative phenotype, but none has yet discussed the application of haplotype-based association analysis to a survival outcome. We describe how the recently proposed Stochastic-EM (SEM) algorithm can be applied to estimate haplotype effects in censored data analysis using a standard Cox proportional hazards formulation. This model has been implemented in the THESIAS software freely available at http://www.genecanvas.org.

Algorithms↗

PubMed2000

Association analysis of the vitamin D receptor gene, the type I collagen gene COL1A1, and the estrogen receptor gene in idiopathic osteoarthritis.

OBJECTIVE: Evidence has accumulated supporting a role for genes in the etiology of osteoarthritis (OA). Several candidates have been targeted as potential susceptibility loci including genes that are involved in the regulation of bone density. Genetic association analysis has suggested a role for the vitamin D receptor gene (VDR) and the estrogen receptor gene (ER) in susceptibility. Such findings must be tested in additional independent cohorts. We tested for association of these 2 genes, plus a third gene implicated in bone density, COL1A1, with idiopathic OA. METHODS: A case-control cohort of 371 affected probands and 369 unaffected spouses was used. Association was tested using 4 intragenic single nucleotide polymorphisms (SNP), one each for the VDR and COL1A1 genes, and 2 for the ER gene. The VDR and ER SNP are the same SNP that have been associated with OA. All 4 SNP affect restriction enzyme sites and were genotyped using polymerase chain reaction and enzyme digestion. Allele and genotype distributions for each SNP were compared between cases and controls and analyzed using Fisher's exact test. RESULTS: There was no evidence of association of the VDR or the ER gene SNP to OA. There was weak evidence of association of the COL1A1 SNP in female cases (p = 0.017), reflected by a difference in the distribution of genotypes at this SNP between female cases and controls (p = 0.027). However, when corrected for multiple testing, these results were not significant. CONCLUSION: If the VDR, ER, or COL1A1 genes do encode predisposition to OA then the 4 SNP tested are not associated with major susceptibility alleles at these 3 loci.

Aged↗

PubMed1999

Novel polymorphism in the promoter and coding regions of the human cholecystokinin B receptor gene: an association analysis with schizophrenia.

Genetic variations in the 5'-untranslated region and the coding region of the CCK-B receptor (CCK-BR) gene were investigated in healthy controls. Novel variants (-215 C-->A, Leu37Phe, Arg319Glu) were found in addition to the mutations (Val125Iso, His207His, Arg215His, 2491 C-->A) reported previously. In the present study, association analysis was carried out for these variants between 80 unrelated schizophrenic patients and 100 healthy controls. The genotype frequency of the -215 C-->A nucleotide substitution in the 5'-untranslated region of CCK-BR gene was significantly higher in the schizophrenic patients than in the controls (6.25%, P = 0.037). However, the difference was not significant after Bonferroni correction for multiple comparisons. Moreover, no association was found between the clinical characteristics of the patients and the genotype frequencies of the variants. These results suggest that the CCK-BR gene polymorphisms have no association with schizophrenia nor its clinical heterogeneity. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:700-704, 1999.

5' Untranslated Regions↗

PubMed2002

Fine mapping of the chromosome 2p12-16 dyslexia susceptibility locus: quantitative association analysis and positional candidate genes SEMA4F and OTX1.

A locus on chromosome 2p12-16 has been implicated in dyslexia susceptibility by two independent linkage studies, including our own study of 119 nuclear twin-based families, each with at least one reading-disabled child. Nonetheless, no variant of any gene has been reported to show association with dyslexia, and no consistent clinical evidence exists to identify candidate genes with any strong a priori logic. We used 21 microsatellite markers spanning 2p12-16 to refine our 1-LOD unit linkage support interval to 12cM between D2S337 and D2S286. Then, in quantitative association analysis, two microsatellites yielded P values<0.05 across a range of reading-related measures (D2S2378 and D2S2114). The exon/intron borders of two positional candidate genes within the region were characterized, and the exons were screened for polymorphisms. The genes were Semaphorin4F (SEMA4F), which encodes a protein involved in axonal growth cone guidance, and OTX1, encoding a homeodomain transcription factor involved in forebrain development. Two non-synonymous single nucleotide polymorphisms were found in SEMA4F, each with a heterozygosity of 0.03. One intronic single nucleotide polymorphism between exons 12 and 13 of SEMA4F was tested for quantitative association, but no significant association was found. Only one single nucleotide polymorphism was found in OTX1, which was exonic but silent. Our data therefore suggest that linkage with reading disability at 2p12-16 is not caused by coding variants of SEMA4F or OTX1. Our study outlines the approach necessary for the identification of genetic variants causing dyslexia susceptibility in an epidemiological population of dyslexics.

Chromosome Mapping↗

PubMed1997

Association analysis of a regulatory variation of the serotonin transporter gene with severe alcohol dependence.

The present study tested the hypothesis that the short, low activity variant of a biallelic polymorphism in the 5' regulatory region of the human serotonin transporter (5-HTT) gene confers susceptibility to severe alcohol dependence marked by severe withdrawal symptoms. Applying a phenotype-genotype strategy, our population-based association analysis included 216 German controls and an extreme sample of 103 severely affected alcoholics who were selected from 315 German alcohol-dependent subjects by a history of alcohol withdrawal seizure or delirium. The frequency of the short allele (S) was significantly increased in the severely affected alcoholics, compared with that in the controls (X2 = 3.87, df = 1, nominal p = 0.049). The post-hoc exploration indicated that this allelic association resulted exclusively from a significant excess of the S/S genotype in the severely affected alcoholics (p = 0.035), suggesting a recessively acting effect. Consistently, we found a weak but significant correlation (p = 0.013) between the frequency of the S/S genotype and severity of withdrawal symptoms (WDS): no WDS [18.3%, odds ratio (OR) = 1.16], vegetative WDS only (21.8%, OR = 1.44), and severe WDS with either withdrawal seizure only or delirium only (25.0%, OR = 1.69), and both withdrawal seizure and delirium (30.8%, OR = 2.30). Further studies are required to test whether the tentative genotype-phenotype relationship occurred by chance or reflects a real genotypic association between a recessively modifying effect of the short variant of the functional 5-HTT promoter polymorphism and alcohol withdrawal vulnerability.

Adult↗

PubMed2002

Essential hypertension and beta2-adrenergic receptor gene: linkage and association analysis.

A region on human chromosome 5 (5q31.1-qter) contains several genes that encode important blood pressure regulators and thus is a good candidate for analysis of linkage and association with hypertension. We recruited 638 individuals from 212 Polish pedigrees with clustering of essential hypertension. These subjects were genotyped for 11 microsatellite markers that span this region to test for linkage to essential hypertension and systolic and diastolic blood pressures. The segment of this region of approximately 7 cM delineated by D5S1480 and D5S500 markers was linked to blood pressures in multipoint analysis. In 2-point analysis, D5S1480--the marker in close proximity to beta2-adrenergic receptor gene--reached the maximal linkage to essential hypertension and adjusted systolic and diastolic blood pressures, implicating this gene as a positional candidate for further association studies. Arg16Gly, Gln27Glu, and Thr164Ile--3 functional single nucleotide polymorphisms within the beta2-adrenergic receptor gene--were tested for association with essential hypertension. None of these polymorphisms showed a significant association with essential hypertension, separately or in the haplotype analysis. This study provided evidence of linkage of 5q31.1-5qter region to essential hypertension in the European population. Moreover, it implicated the chromosomal segment in close proximity to D5S1480 and D5S500. The detailed analysis of 3 single nucleotide polymorphisms does not support the role of the beta2-adrenergic receptor gene as a major causative gene for the detected linkage.

Adult↗

PubMed2005

Association analysis of tissue inhibitor of metalloproteinase2 gene polymorphisms with COPD in Egyptians.

Proteinase/antiproteinase imbalance is recognized to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). A relative increase in the activities of matrix metalloproteinases might be caused by mutations of tissue inhibitor of metalloproteinase2 (TIMP2). Recently, two polymorphisms of the TIMP2 gene, +853 G/A and -418 G/C (+551 and -720 from the translation initiation site), have been shown to be associated with the development of COPD in the Japanese population. In this study, a case-control association analysis for these polymorphisms was conducted in the Egyptian population using 106 COPD patients and 72 healthy controls. The genotype frequency of +853 G/A was significantly different between the patient and the control groups (P = 0.029), although no significant difference was detected in the allele frequency between the two groups. These results suggest that the +853 G/A polymorphism of the TIMP2 gene might be associated with COPD across ethnicities. In contrast, neither the distributions of genotype nor allele frequencies of -418 G/C were significantly different between the two groups, raising the possibility that a combination of different genetic factors contributes to the development of COPD in different ethnic groups.

Case-Control Studies↗

PubMed2003

Localization of a non-melanoma skin cancer susceptibility region within the major histocompatibility complex by association analysis using microsatellite markers.

The major histocompatibility complex (MHC) is known to have a role in the development of non-melanoma skin cancer (NMSC), although the genes and mechanisms involved have yet to be determined. To identify the susceptibility locus for NMSC within the MHC, we used a collection of well-defined polymorphic microsatellite markers from the Human leucocyte antigen (HLA) region for an association analysis of 150 cases with NMSC and 200 healthy controls selected from the Busselton population in Western Australia. High-resolution mapping was undertaken using a total of 40 highly polymorphic markers located at regular intervals across the HLA region (3.6Mb). Polymerase chain reaction (PCR) analysis was initially performed on pooled DNA markers to detect those markers that showed different allele profiles. Statistically significant differences in allelic frequencies (differentiating alleles) were found between cases and controls at three polymorphic microsatellite loci within a 470-kb genomic susceptibility region ranging between 6 kb centromeric of the HLA-B gene and intron 5 of the DDR gene. Interestingly, this genome region corresponded completely with the psoriasis-susceptibility locus. The three differentiating alleles and another four markers outside the susceptibility region were then PCR tested by individual genotyping of cases and controls. The newly identified susceptibility locus for NMSC within the MHC was found to be significantly different between the cases and controls by comparisons of allele frequencies at the three differentiating loci estimated from DNA pools and then confirmed by individual genotyping. This is the first study using high density microsatellite markers to localize a NMSC susceptibility region within the human genome.

Australia↗

PubMed2004

A new algorithm for haplotype-based association analysis: the Stochastic-EM algorithm.

It is now widely accepted that haplotypic information can be of great interest for investigating the role of a candidate gene in the etiology of complex diseases. In the absence of family data, haplotypes cannot be deduced from genotypes, except for individuals who are homozygous at all loci or heterozygous at only one site. Statistical methodologies are therefore required for inferring haplotypes from genotypic data and testing their association with a phenotype of interest. Two maximum likelihood algorithms are often used in the context of haplotype-based association studies, the Newton-Raphson (NR) and the Expectation-Maximisation (EM) algorithms. In order to circumvent the limitations of both algorithms, including convergence to local minima and saddle points, we here described how a stochastic version of the EM algorithm, referred to as SEM, could be used for testing haplotype-phenotype association. Statistical properties of the SEM algorithm were investigated through a simulation study for a large range of practical situations, including small/large samples and rare/frequent haplotypes, and results were compared to those obtained by use of the standard NR algorithm. Our simulation study indicated that the SEM algorithm provides results similar to those of the NR algorithm, making the SEM algorithm of great interest for haplotype-based association analysis, especially when the number of polymorphisms is quite large.

Algorithms↗

PubMed2000

Novel polymorphisms of the human cholecystokinin A receptor gene: an association analysis with schizophrenia.

The cholecystokinin A receptor (CCK-AR) modulates CCK-stimulated dopamine release in the posterior nucleus accumbens, and its gene is mapped to 4p15.2-15.1 with the dopamine receptor 5 (DR5) gene. We speculated that alterations in the CCK-AR lead to an increase in dopamine release, which may in turn constitute a predisposition in schizophrenia. We investigated genetic variations in the promoter region and the coding region of the CCK-AR gene. An association analysis was conducted between 83 unrelated schizophrenic patients and 80 healthy controls. Novel polymorphisms (201A-->G, 246G-->A in the promoter region, 1260T-->A, 1266T-->C in intron 1 within the 3' mRNA splice acceptor site consensus sequence, and Leu306Leu in exon 5) were found in addition to the variants (608G-->A in intron 1, 3849C-->T [Ile296Ile] in exon 5) reported previously. Significant differences were found in the allele frequencies of the 201A-->G nucleotide substitution in the promoter region between patients and controls (P = 0.0181, odds ratio: 1.972, after Bonferroni correction: P = 0.0543). These differences were also found between the patients with paranoid type and controls (P = 0.0274, odds ratio = 3.667, after Bonferroni correction: P = 0.0822). Our analyses suggest that the 201A allele frequency was higher in the schizophrenic group, especially in the paranoid type, than in the control group at a rate that was not quite significant after Bonferroni correction. Am J. Med Genet. (Neuropsychiatr. Genet.) 96:141-145, 2000.

Adult↗

PubMed2003

Human nuclear transcription factor gene CREM: genomic organization, mutation screening, and association analysis in panic disorder.

Panic disorder is an anxiety disorder with an estimated heritability of 48%. Variation in the gene of the nuclear transcription factor "cAMP-responsive element modulator" (CREM) might contribute to its pathogenesis. CREM knock-out mice exhibit significantly less anxiety behavior than wild-type mice and the alternative CREM gene product "inducible cAMP early repressor" (ICER) plays a pivotal role in the hypothalamo-pituitary-adrenal (HPA) axis, which is disturbed in panic disorder. We characterized the genomic organization of the human CREM gene and performed a systematic mutation screening by means of single stranded conformational analysis (SSCA) in a sample of 40 German patients with panic disorder (DSM-III-R). Four novel single nucleotide polymorphisms in CREM promoters P 1 and P 4, one trinucleotide (ATT)-repeat polymorphism in CREM promoter P 2-generating the ICER isoform-and a rare amino acid substitution in CREM exon glut 2 were identified. Association analysis in an extended sample of German patients (n = 88) revealed a significant excess of the shorter CREM P 2 promoter eight-repeat trinucleotide allele and of genotypes containing the eight-repeat trinucleotide allele in panic disorder (P = 0.02), in particular in panic disorder without agoraphobia (P = 0.001). A replication study in independent Italian (n = 76) and Spanish (n = 62) samples, however, failed to confirm this observation. This suggests that the CREM P 2 promoter trinucleotide polymorphism is not a major susceptibility factor in the pathogenesis of panic disorder. Functional analysis of the observed CREM P 2 promoter polymorphism as well as studies in independent panic disorder samples are necessary.

Agoraphobia↗

PubMed1991

Orienting, habituation, and resource allocation: an associative analysis.

This paper addresses the question of the most appropriate theoretical account of the phenomena of orienting and habituation. Several lines of evidence are reviewed. First, it is argued that the effects of stimulus omission require a comparator theory in which it is asserted that responses to iterated events result from a comparison between predicted and actual stimulus input. Second, the data from studies in which paired stimulus events are employed seem, at least at first sight, to be best explained in terms of a comparator theory in which a key role is ascribed to associative processes. Third, secondary task probe reaction time data indicate that events that elicit orienting also command processing resources, and that habituation involves changes in the manner in which events are processed. Finally, recent data on the effects of intermodality change indicate that electrodermal responses are larger on the change trial than on the first habituation training trial; these results seem problematical for noncomparator theories. However, other data on the context-specificity of habituation and on the effects of stimulus miscuing cast doubt on the usefulness of an associative analysis as a general account of habituation phenomena. Nevertheless, the weight of evidence seems to indicate that an adequate theory of human habituation must include a comparison process and must acknowledge that orienting and habituation involve a re-allocation of attentional resources.

Arousal↗

PubMed1994

Multiple DNA variant association analysis: application to the insulin gene region in type I diabetes.

Association and linkage studies have shown that at least one of the genetic factors involved in susceptibility to insulin-dependent diabetes mellitus (IDDM) is contained within a 4.1-kb region of the insulin gene. Sequence analysis has led to the identification of 10 DNA variants in this region that are associated with increased risk for IDDM. These variants are in strong linkage disequilibrium with each other, and previous studies have failed to distinguish between the variant(s) that cause increased susceptibility to IDDM and others that are associated with the disease because of linkage disequilibrium. To address this problem, we have undertaken a large population study of French diabetics and controls and have analyzed genotype patterns for several of the variant sites simultaneously. This has led to the identification of a subset consisting of four variants (-2733AC, -23HphI, -365VNTR, and +1140AC), at least one of which appears to be directly implicated in disease susceptibility. The multiple-DNA-variant association-analysis approach that is applied here to the problem of identifying potential susceptibility variants in IDDM is likely to be important in studies of many other multifactorial diseases.

Diabetes Mellitus, Type 1↗

PubMed1990

Recovery of components of fluorescence spectra of mixtures by intensity- and anisotropy decay-associated analysis: the bacterial luciferase intermediates.

Reaction of FMNH2 and O2 with bacterial luciferase followed by blue light irradiation results in a product previously claimed to have the same fluorescence spectral distribution as the bioluminescence. Preparations of this "high fluorescence" intermediate, however, contain two fluorescent components, one from the intermediate and the other its breakdown product, FMN. Since the intermediate has a fluorescence lifetime of around 10 ns and a rotational correlation time in the range of 100 ns, compared to 5.0 and 0.15 ns, respectively, for the FMN, the two components can be successfully resolved from the total fluorescence by an anisotropy decay- and fluorescence decay-associated analysis employing simultaneous global computational methods. The fluorescence spectra of the intermediates from two types of luciferase were analyzed in this way; one luciferase was from Vibrio harveyi and the other was from an unusual type of V. fischeri that had an in vivo bioluminescence maximum at 505 nm, a wavelength almost 20 nm longer than that of the V. harveyi bioluminescence. For V. harveyi the true fluorescence of the intermediate is distinct from the bioluminescence, being found at a wavelength about 10 nm longer. For the type of V. fischeri examined, any difference in the two spectra is less certain. A control experiment with the dye 8-amino-1- naphthalenesulfonate bound to BSA and mixed with FMN recovered the original spectrum of the bound dye accurately.

Animals↗

PubMed2026

Genome-Wide Association Analysis of Hippocampal Neuroplasticity as an Indicator of Stress Responsiveness in Laying Hens (Gallus gallus domesticus).

Environmental stressors in commercial poultry systems can negatively affect bird welfare, although individuals vary considerably in their responses. Neuroplasticity within the hippocampus, measured through the density of doublecortin-positive (DCX+) neurons, provides a potential biomarker of stress experience in laying hens. However, the genetic basis underlying variation in this biomarker remains poorly understood. A total of 42 H&N and Hy-Line Brown hens housed in a multitier free range and enriched cage system, respectively, were genotyped using Genotyping by Sequencing, yielding over 200 000 SNP markers after initial filtering. Hippocampal tissue sections were immunostained for DCX to quantify the density of highly plastic neurons. A genome-wide association analysis identified 19 genomic regions across eight chromosomes within the top 1% of windows explaining the greatest proportion of genetic variance in the neuroplasticity phenotype. Within ±100 kb of these regions, 39 annotated genes were identified, several of which are involved in cellular regulation and genetic information processing pathways. Notably, PIK3R6, VPS37D, STX1A, BAZ1B, HGH1, MAF1, MAPK15, and PIT54 emerged as positional candidate genes potentially contributing to variation in stress responsiveness. These findings provide preliminary insight into the genetic architecture of hippocampal neuroplasticity in laying hens and highlight candidate genes that may contribute to individual differences in stress response, with potential implications for breeding strategies aimed at improving poultry welfare.

Animals↗

PubMed2006

Association analysis of adiponectin and somatostatin polymorphisms on BTA1 with growth and carcass traits in Angus cattle.

This study tested positional candidate genes adiponectin (ADIPOQ) and somatostatin (SST) for effects on carcass traits in a commercially relevant cattle population. Both genes are located within a region of BTA1 previously reported to harbour quantitative trait loci (QTL) that affect marbling, quality grade, yield grade, ribeye area and weaning weight in Bos taurus x Bos indicus crosses. Except for the first intron of ADIPOQ, both genes, including over 2 kb upstream of the promoters, were sequenced in five registered Angus sires to identify polymorphisms. A variable copy duplication and three single nucleotide polymorphisms (SNPs) in ADIPOQ and one SNP in SST were genotyped and tested for association with 19 traits in a 14-generation pedigree of 1697 registered Angus artificial insemination sires representing all the major USA lineages of the breed. Linear models that parameterized predicted genetic merits in terms of allele substitution effects were fit by weighted least squares, and goodness-of-fit tests were employed to differentiate causal mutations or polymorphisms in strong linkage disequilibrium (LD) with causal mutations from markers in weak LD with QTL. We confirmed the presence of QTL affecting marbling, ribeye muscle area and fat thickness in the vicinity of SST and ADIPOQ on BTA1 in Angus; excluded SST as underlying the ribeye muscle area QTL; and excluded ADIPOQ as underlying the marbling score QTL. However, association analysis provides very limited information about QTL location and has little intrinsic value when performed in the absence of linkage or LD analysis using flanking marker data to localize the QTL effect relative to positional candidate genes.

Adiponectin↗

PubMed2003

Elemental analysis of glass fragments by ICP-MS as evidence of association: analysis of a case.

Inductively coupled plasma mass spectrometry (ICP-MS) was used to analyze glass evidence from a case in which a person broke a window in each of 15 vehicles in a parking lot in order to gain entry into the vehicles. The results of the analysis by traditional methods, which measure the properties of color, thickness, density, and refractive index, are also reported. A total of 15 known samples representing the windows on the cars and 42 questioned glass fragments recovered from the suspect and the police vehicle where the suspect was sitting were submitted for analysis. Density comparisons separated one of the known samples into three samples, increasing the number of known samples from 15 to 17. The concentrations of 16 elements were measured for all but three of the samples using an external calibration ICP-MS method with internal standardization. Color assessment (non-instrumental) separated the 17 known samples into two groups, and refractive index measurements resulted in six groups when the Emmons double variation method was used and ten groups when the Glass Refractive Index Measurement 2 (GRIM2) system was used. Elemental analysis, by itself, differentiated all of the known samples from each other and associated four of the known sample fragments with several of the questioned sample fragments. The informing power of RI, density, and elemental analysis comparisons is evaluated and a summary of the case results is reported.

Journal Article↗