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At least 1,207 records · Page 67Linked to original sources
PubMed2006

Distinguishable haplotype blocks in the HTR3A and HTR3B region in the Japanese reveal evidence of association of HTR3B with female major depression.

BACKGROUND: Genetic variations in the serotonin receptor 3A (HTR3A) and 3B (HTR3B) genes, positioned in tandem on chromosome 11q23.2, have been shown to be associated with psychiatric disorders in samples of European ancestry. But the polymorphisms highlighted in these reports map to different locations in the two genes, therefore it is unclear which gene exerts a stronger effect on susceptibility. METHODS: To determine the haplotype block structure in the genomic regions of HTR3A and HTR3B, and to examine whether genetic variations in the region show evidence of association with schizophrenia and affective disorder in the Japanese, we performed haplotype-based case-control analysis using 29 polymorphisms. RESULTS: Two haplotype blocks each were revealed for HTR3A and HTR3B in Japanese samples. In HTR3B, haplotype block 2 that included a nonsynonymous single nucleotide polymorphism (SNP), yielded evidence of association with major depression in females (global p = .0023). Analysis employing genome-wide SNPs using the STRUCTURE program did not detect population stratification in the samples. CONCLUSIONS: Our results suggest an important role for HTR3B in major depression in women and also raise the possibility that previously proposed disease-associated SNPs in the HTR3A/B region in Caucasians are in linkage disequilibrium with haplotype block 2 of HTR3B in the Japanese.

Adult↗
PubMed2002

A single-strand conformation polymorphism method for the large-scale analysis of mutations/polymorphisms using capillary array electrophoresis.

We present a high-throughput single-strand conformation polymorphism (SSCP) method, performed on a commercially available capillary array DNA sequencer. We tested various sieving matrices and electrophoretic conditions, using 51 DNA fragments which included 45 fragments carrying only one single nucleotide polymorphism (SNP), 4 fragments having two SNPs and 2 fragments with insertion or deletion. Resolution of alleles was improved by increasing concentrations of both sieving matrices and buffers, and all examined polymorphisms of DNA fragments were detected, most of them (45 fragments) as clearly split allele peaks in heterozygotes. Allele frequencies of SNPs can be estimated accurately by determining the relative amounts of alleles in pooled DNA. In this method, the turn-around time for the analysis of 96 samples is less than 3 h. These results demonstrate that capillary array-based SSCP is an efficient and accurate technique for the large-scale quantitative analysis of mutations/polymorphisms.

DNA Mutational Analysis↗
PubMed2002

Gene-based SNP genetic association study of the corticotropin-releasing hormone receptor-2 (CRHR2) in major depression.

An increasing amount of data suggests that affective disorders are related to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, the stress-response system. Corticotropin-releasing hormone receptor-2 (CRHR2)-deficient mice display a stress-sensitive and anxiety-like phenotype suggesting that the CRHR2 is a plausible functional candidate gene influencing the reactivity of the HPA axis and therefore the liability to develop affective disorders. In this study, a gene-based single nucleotide polymorphism (SNP) map of the corticotropin-releasing hormone receptor 2 (CRHR2) was constructed containing one synonymous cSNP in exon 10, two intronic SNPs, and two SNPs in the 5' upstream regulatory region. No significant difference in allele or genotype frequency was found for four out of the five SNPs between Belgian unipolar (UP) patients and age-, gender-, and ethnicity-matched controls. The cSNP did show allelic and genotypic association with borderline significance (P=0.04). However, a replication study of this cSNP in a bipolar sample of Belgian origin and a Swedish UP sample did not show significant differences in allele and genotype frequencies.

DNA↗
PubMed2026

Leveraging ONT move table values for signal aware variant calling.

Oxford Nanopore Technologies (ONT) sequencing enables long-range haplotype phasing and contiguous genome assembly but still exhibits elevated error rates that challenge small variant calling, particularly for insertions and deletions (Indels). While raw electrical signals contain rich information, existing signal-aware methods require computationally intensive processing of large signal files. Here, we present Clair3 v2, a method that leverages the ONT move table-a lightweight byproduct of basecalling that maps signal events to nucleotide positions-to improve variant calling accuracy. Clair3 v2 builds upon Clair3 and integrates signal-level dwelling time to significantly enhance variant calling performance. We also propose a genome position based circular buffer to incorporate dwelling time with minimal computational overhead. Benchmarking across six Genome in a Bottle samples demonstrates substantial improvements in variant calling accuracy. With HAC basecalling, Clair3 v2 achieves a mean SNP F1-score of 97.69% at 10 × depth (compared to 96.45% for baseline Clair3), and Indel F1 scores improved from 64.27% to 76.70%, while gains persisted at higher depths. The benefits were most pronounced for longer Indels and in complex genomic regions, where Indel F1 scores in long homopolymer regions improved from 14.3% to 45.2%. Benchmark results across various basecalling modes, samples, and coverage settings outperformed Clair3 baselines and other methods, including DeepVariant and Dorado Variant, and demonstrate the significant benefits of Clair3 v2. Furthermore, Clair3 v2 incurs negligible runtime compared to standard Clair3, making it practical for routine use.

Sequence Analysis, DNA↗
PubMed2004

Proteomic studies identified a single nucleotide polymorphism in glyoxalase I as autism susceptibility factor.

Autism is a neurodevelopmental disability characterized by deficits in verbal communications, impairments in social interactions, and repetitive behaviors. Several studies have indicated strong involvement of multigenic components in the etiology of autism. Linkage analyses and candidate gene search approaches so far have not identified any reliable susceptibility genes. We are using a proteomic approach to identify protein abnormalities due to aberrant gene expression in autopsied autism brains. In four of eight autism brains, we have found an increase in polarity (more acidic) of glyoxalase I (Glo1) by two-dimensional gel electrophoresis. To identify the molecular change resulting in the shift of Glo1 polarity, we undertook sequencing of GLO1 gene. Direct sequencing of GLO1 gene/mRNA in these brains, has identified a single nucleotide polymorphism (SNP), C419A. The SNP causes an Ala111Glu change in the protein sequence. Population genetics of GLO1 C419A SNP studied in autism (71 samples) and normal and neurological controls (49 samples) showed significantly higher frequency for the A419 (allele frequency 0.6 in autism and 0.4 in controls, one-tailed Fisher's test P < 0.0079). Biochemical measurements have revealed a 38% decrease in Glo1 enzyme activity in autism brains (one-tailed t-test P < 0.026). Western blot analysis has also shown accumulation of advanced glycation end products (AGE's) in autism brains. These data suggest that homozygosity for A419 GLO1 resulting in Glu111 is a predisposing factor in the etiology of autism.

Adolescent↗
PubMed2004

A glycogen synthase kinase 3-beta promoter gene single nucleotide polymorphism is associated with age at onset and response to total sleep deprivation in bipolar depression.

The molecular mechanisms driving the biological clock in the suprachiasmatic nucleus of the hypothalamus may play a role in mood disorders. A single nucleotide polymorphism (SNP) (-50T/C) falling into the effective promoter region (nt -171 to +29) of the gene coding for glycogen synthase kinase 3-beta (GSK3-beta) has been linked with different age at onset of bipolar illness. GSK3-beta codes for an enzyme which is a target for the action of lithium and valproic acid, and the inhibition of which causes antidepressant-like behaviors in a preclinical model. We studied the effect of this polymorphism on the acute response to total sleep deprivation of 60 depressed bipolar type I inpatients. Homozygotes for the mutant allele of GSK3-beta promoter (-50T/C) SNP showed a later onset of bipolar illness, and better acute effects of TSD treatment on perceived mood (as rated on VAS). Overall, these observations suggest a protective role for this genotype in respect to bipolar illness. Results warrant interest for the variants of genes pertaining to the molecular clock as possible endophenotypes of bipolar disorder, and for GSK3-beta as a target of a new class of antidepressant drugs, but caution ought to be taken in interpreting these preliminary results and future replication studies must be awaited because of the low frequency of the GSK3-beta*C/C genotype in the studied populations.

Adult↗
PubMed2005

[Application of DHPLC in human genomic SNP screening and genotyping for all-trans-retinol dehydrogenase].

OBJECTIVE: To assess the efficacy of denaturing high-performance liquid chromatography (DHPLC) as a new screening assay for sequence variation in SNP detecting and new approach to SNP genotyping. METHODS: DHPLC was used to screen SNPs in 8 DNA pools each consisting of DNA from 5 individuals, and genotype the identified SNPs in 150 Chinese subjects from Hong Kong. RESULTS: Seventeen SNPs were identified: 12 were novel and 5 were previously reported; 11 were found in screening stage and the other 6 were found in genotyping stage; 2 were only found in Caucasian samples; 3 showed ethnic difference of minor allele frequency(MAF); 7 were common with the MAF>0.05 in Chinese samples. CONCLUSION: The results demonstrated the efficiency of DHPLC in screening SNPs when coupled with DNA pooling strategy, and in genotyping SNPs.

Alcohol Oxidoreductases↗
PubMed2005

Association tests of interleukin-6 (IL-6) and type II tumor necrosis factor receptor (TNFR2) genes with bone mineral density in Caucasians using a re-sampling approach.

Interleukin 6 (IL-6) and tumor necrosis factor (TNF) are important cytokines for bone turnover. In this study, a promoter C-174G single-nucleotide polymorphism (SNP) within the IL-6 gene affecting the transcription rate of IL-6 and an exon 6 T676G SNP of the TNF receptor 2 (TNFR2) gene causing an M196R amino-acid change were examined for their relationship with bone mineral density (BMD). Four hundred and five multi-offspring Caucasian families, including 389 male children and 744 female children, were used. One thousand re-samplings were conducted and in each data set, one child was randomly chosen from each family. For each data set, one-way analysis of variance (ANOVA) test was independently implemented using age, age2, sex, height and weight as covariates. There were 523, 288, 204 and 369 significant results out of 1,000-replicate re-samplings of the data of the IL-6 SNP (P<0.05) for one-third, mid-distal, ultradistal radius BMD, and the first principal component (PC1) extracted from the three radial BMDs, respectively, which means that the confidences for associations of the C-174G SNP in the IL-6 gene with one-third, mid-distal, ultradistal radius (totally called distal forearm) BMDs, and PC1, were 52.3, 28.8, 20.4 and 36.9%, respectively. For this SNP with BMD at other skeletal sites and the TNFR2 T676G SNP with BMD at any site, significant results were far less than 200 times out of 1,000 re-sampling replicates. The exceedingly consistent permutation results further improved the confidence of the associations. It may imply that the IL-6 C-174G SNP is associated with distal forearm BMD, but there is no evidence that the TNFR2 T676G SNP is related with BMD in US Caucasians. This is the first attempt to conduct association test utilizing a re-sampling approach. Our results may be more informative than other association analyses that were only based on one sampling result. The results also suggest that different samplings could produce significantly diverse results even for the same population and the results from one sampling are unlikely to be conclusive. Our results have significant implications for association studies and interpretation of non-reproducible association findings.

Body Weights and Measures↗
PubMed2005

The R620W C/T polymorphism of the gene PTPN22 is associated with SLE independently of the association of PDCD1.

The gene PTPN22 is located on chromosome 1p13 and encodes a protein tyrosine phosphatase called the lymphoid-specific phosphatase (Lyp). Lyp is expressed in lymphocytes, where it physically associates through its proline-rich motif (called P1) with the SH3 domain of the protein tyrosine kinase Csk, an important suppressor of the Src family of kinases Lck and Fyn, which mediate TCR signaling. Therefore, it is said that interaction between Lyp and Csk enables these effectors to inhibit T-cell activation synergistically. It was reported that a missense single nucleotide polymorphism , R620W (rs2476601), 1858C->T encodes an amino-acid change in the P1 proline-rich motif of the gene PTPN22 and is associated with SLE in North American white individuals. PTPN22 gene polymorphisms were genotyped in 571 Swedish SLE patients and 1042 healthy controls using TaqMan SNP Genotyping Assay. Differences were observed between cases and control subjects at both the allele (chi(2)=11.2895;P=0.0007,1df) and genotype (chi(2)=10.2243;P=0.0013, 1df) levels. We also found evidence of a genetic association between PTPN22 and renal disorder (chi(2)=9.5660;P=0.0019). We then analyzed if in patients with renal disorder associations with PDCD1 and PTPN22 were independent. Our data suggest that this appears to be the case although we observed some degree of interaction.

Alleles↗
PubMed2006

Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance.

PURPOSE: Although single nucleotide polymorphisms (SNP) of the dihydropyrimidine dehydrogenase gene (DPYD) have been reported, which affect enzyme activity and the severity of 5-fluorouracil (5-FU) toxicity, no pretherapeutic detection has thus far been developed. We investigated 22 DPYD gene SNPs, their respective incidence, their link with grade 3 to 4 toxic side effects, and their management in practice: 9 were looked for in 487 patients, whereas 13 others were investigated in 171 patients. PATIENTS AND METHODS: SNPs were detected before 5-FU-based treatment in WBC using a Pyrosequencing method. Close clinical and biological follow-up was done. RESULTS: Five different SNPs were found in 187 patients (IVS14 + 1G>A, 2846A>T, 1679T>G, 85T>C, -1590T>C). Three hundred patients had no SNP. Forty-four patients had grade 3 to 4 toxic side effects in either the first or second cycle. Sixty percent of patients with either IVS14 + 1G>A or 2846A>T SNPs and the only patient with 1679T>G SNP experienced early grade 3 to 4 toxicity, compared with 0%, 5.5%, and 15% of those with either -1590T>C, 85T>C SNP, or no SNP, respectively. In cases with grade 3 to 4 toxicity, treatment either had to be quickly stopped, or could be safely continued with an individual dose adjustment. Sensitivity, specificity, and positive and negative predictive values of the detection of these three major SNPs as toxicity predictive factors were 0.31, 0.98, and 0.62 and 0.94, respectively. CONCLUSION: Pretreatment detection of three DPYD SNPs could help to avoid severe toxic side effects. This approach is suitable for clinical practice and should be compared or combined with pharmacologic approaches. In the case of dihydropyrimidine dehydrogenase deficiency, 5-FU administration often can be safely continued with an individual dose adjustment.

Aged↗
PubMed2003

Positive association of the AMPA receptor subunit GluR4 gene (GRIA4) haplotype with schizophrenia: linkage disequilibrium mapping using SNPs evenly distributed across the gene region.

The glutamatergic dysfunction hypothesis suggests that genes involved in the glutamate neurotransmitter system are candidates for schizophrenia-susceptibility genes. We have been conducting systematic studies of the association between glutamate receptors and schizophrenia. We report on a positive association of some haplotypes of the AMPA receptor subunit GluR4 gene (GRIA4) with schizophrenia. We genotyped 100 Japanese schizophrenics and 100 controls for six single nucleotide polymorphism (SNP) markers distributed at intervals of about 50 kb in the GRIA4 region, and estimated the degree of linkage disequilibrium (LD) between the SNPs. We constructed haplotypes of the SNPs in LD using the EM algorithm to test their association with schizophrenia. Significant associations were detected for the combination of SNP4-5 (chi(2) = 12.54, df = 3, P = 0.0057, P = 0.029 with Bonferroni correction) and for the combination of SNP3-4-5 (chi(2) = 18.9, df = 7, P = 0.0085, P = 0.043 with Bonferroni correction). These results suggest that at least one susceptibility locus for schizophrenia is located within or very close to the GRIA4 region in Japanese.

Alleles↗
PubMed2006

Identification of genetic variation and putative regulatory regions in bovine CARD15.

Mutations in caspase recruitment domain 15 (CARD15) are associated with susceptibility to Crohn's disease and Blau Syndrome. We performed comparative analyses of the bovine, murine, and human CARD15 transcripts to elucidate functionality of bovine CARD15 and examine its potential role in bovine disease resistance. Comparative analyses of intronic sequence across seven divergent species were performed to identify putative regulatory element binding motifs. High levels of interspecies conservation in sequence, genomic structure, and protein domains were detected indicating common functionality for CARD15 in cattle, human, and mouse. We identified species-specific regulatory elements in the 5' and 3' untranslated regions, suggesting that modes of regulation may have diverged across species. Thirty-one conserved putative regulatory element binding motifs were identified in the CARD15 intronic sequence of seven species. To assess the extent of genetic diversity within bovine CARD15, 41 individuals from two subspecies were sequenced and screened for polymorphisms. Thirty-six single nucleotide polymorphisms (SNPs) were identified. Finally, 20 subspecies-specific haplotypes were predicted with 7 and 13 unique haplotypes explaining the diversity within B. taurus taurus and B. taurus indicus animals, respectively. Strong evidence for a simple causal relationship between these SNP loci and their haplotypes with Johne's disease was not detected.

3' Untranslated Regions↗
PubMed2005

ALOHOMORA: a tool for linkage analysis using 10K SNP array data.

SUMMARY: ALOHOMORA is a software tool designed to facilitate genome-wide linkage studies performed with high-density single nucleotide polymorphism (SNP) marker panels such as the Affymetrix GeneChip(R) Human Mapping 10K Array. Genotype data are converted into appropriate formats for a number of common linkage programs and subjected to standard quality control routines before linkage runs are started. ALOHOMORA is written in Perl and may be used to perform state-of-the-art linkage scans in small and large families with any genetic model. Options for using different genetic maps or ethnicity-specific allele frequencies are implemented. Graphic outputs of whole-genome multipoint LOD score values are provided for the entire dataset as well as for individual families. AVAILABILITY: ALOHOMORA is available free of charge for non-commercial research institutions. For more details, see http://gmc.mdc-berlin.de/alohomora/

Algorithms↗
PubMed2006

Polymorphisms in DNA damage binding protein 2 (DDB2) and susceptibility of primary lung cancer in the Chinese: a case-control study.

DNA damage binding protein 2 (DDB2) is one of the major DNA repair proteins involved in the nucleotide excision repair (NER) pathway. Mutations in the DDB2 gene can cause a repair-deficiency syndrome xeroderma pigmentosum group E. Because tobacco carcinogens can cause DNA damage that is repaired by NER and suboptimal NER capacity is reported to be associated with lung cancer risk, we hypothesized that common variants in the DDB2 gene are associated with lung cancer risk. To test this hypothesis, we conducted a case-control study of 1010 patients with incident lung cancer and 1011 cancer-free controls and genotyped two DDB2 single nucleotide polymorphisms (SNPs) (rs830083 and rs3781620) that are in linkage disequilibrium with other untyped SNPs. We found that compared with the rs830083CC, subjects carrying the heterozygous rs830083CG genotype had a significantly 1.31-fold increased risk of lung cancer [95% confidence interval (CI) 1.08-1.60] and those carrying the homozygous rs830083GG genotype had a non-significantly 1.22-fold elevated risk (95% CI 0.89-1.67). In addition, effects of the combined rs830083CG/GG variant genotypes were more evident in young subjects, heavy smokers and subjects with a positive family history of cancer. These findings indicate, for the first time, that the DDB2 rs830083 polymorphism may contribute to the etiology of lung cancer. Further functional studies on this SNP and/or related variants are warranted to elucidate the underlying molecular mechanisms of the association.

Aged↗
PubMed2003

[Relationship between the Fnu4HI site polymorphism of monoamine oxidase A gene and Parkinson's disease].

OBJECTIVE: To study the association between the polymorphism of human monoamine oxidase type A (MAO-A) gene and Parkinson's disease(PD). METHODS: Fnu4HI restriction fragment length polymorphism(RFLP) and PCR-RFLP were used to detect the mutation of MAO-A gene. The frequencies of alleles and genotypes at the MAO-A Fnu4HI locus on the X chromosome in different PD group were compared with those of the control group. RESULTS: It was found that the frequencies of G allele in the patients with PD and controls were 0.613 and 0.527 respectively, P=0.039 "the frequencies of TT genotype were 0.303 and 0.415(P=0.014), and the frequencies of GG genotype were 0.564 and 0.451 respectively(P=0.021). When the patients were divided into two groups by age-onset, significant difference in the allelic and genotypic frequencies was observed only between early-onset PD group and control group. And when the PD patients were grouped by sex, significant difference was observed only between male PD group and male control group (the frequencies of G allele being 0.669 and 0.500 respectively, P=0.005). CONCLUSION: This study revealed significant differences between PD group and control group in allelic and genotypic frequencies. The findings supported the hypothesis about an association between MAO-A gene and PD, suggesting that age at onset of PD and gender predisposition might be related to the putative association, and Fnu4HI SNP be a risk factor for PD.

Alleles↗
PubMed2005

Estimating SNP proportions in populations of malaria parasites by sequencing: validation and applications.

We have developed a rapid and simple method for determining accurately the proportions of alleles or individual malaria clones in a mixed infection. The technique uses a nested PCR reaction to amplify, from parasite mixtures, alleles of genes differing by single nucleotide polymorphisms, simultaneously, using common primers to non-polymorphic sequences. The mixed products are sequenced, and the heights of fluorescence peaks associated with different nucleotides at the polymorphic site used to quantitate the proportions of each allele in the mixture. We have confirmed the accuracy and precision of the method using a set of well-validated mixtures of genetically different malaria parasites. This technique can be used in the mapping of genetic loci underlying phenotypic traits and in the evaluation of the effects of different alleles upon the reproductive success (fitness) of parasites.

Animals↗
PubMed2002

A surface invasive cleavage assay for highly parallel SNP analysis.

The structure-specific invasive cleavage of single-stranded DNA by 5' nucleases is a useful means for sensitive detection of single-nucleotide polymorphisms or SNPs. The solution-phase invasive cleavage reaction has sufficient sensitivity for direct detection of as few as 600 target molecules with no prior target amplification. One approach to the parallelization of SNP analysis is to adapt the invasive cleavage reaction to an addressed array format. Two surface invasive cleavage reaction strategies were designed and tested using the polymorphic site in codon 158 of the human ApoE gene as a model system, with a synthetic oligonucleotide as target. The upstream oligonucleotide, which is required for the invasive cleavage reaction, was either added in solution (strategy 1), or co-immobilized on the surface along with the probe oligonucleotide (strategy 2). Both strategies showed target-concentration and time-dependent amplification of signal. Parameters that govern the rate of the surface-invasive cleavage reactions are discussed.

Apolipoproteins E↗
PubMed2002

Testing for population subdivision and association in four case-control studies.

Population structure has been presumed to cause many of the unreplicated disease-marker associations reported in the literature, yet few actual case-control studies have been evaluated for the presence of structure. Here, we examine four moderate case-control samples, comprising 3,472 individuals, to determine if detectable population subdivision is present. The four population samples include: 500 U.S. whites and 236 African Americans with hypertension; and 500 U.S. whites and 500 Polish whites with type 2 diabetes, all with matched control subjects. Both diabetes populations were typed for the PPARg Pro12Ala polymorphism, to replicate this well-supported association (Altshuler et al. 2000). In each of the four samples, we tested for structure, using the sum of the case-control allele frequency chi(2) statistics for 9 STR and 35 SNP markers (Pritchard and Rosenberg 1999). We found weak evidence for population structure in the African American sample only, but further refinement of the sample, to include only individuals with U.S.-born parents and grandparents, eliminated the stratification. Our examples provide insight into the factors affecting the replication of association studies and suggest that carefully matched, moderate-sized case-control samples in cosmopolitan U.S. and European populations are unlikely to contain levels of structure that would result in significantly inflated numbers of false-positive associations. We explore the role that extreme differences in power among studies, due to sample size and risk-allele frequency differences, may play in the replication problem.

Case-Control Studies↗