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PubMed2026

Correlations between causal effect sizes of proximal SNPs vary with functional annotations and implicate stabilizing selection.

Causal disease effect sizes of proximal single-nucleotide polymorphisms (SNPs) are widely assumed to be independent but could be correlated. Here we introduce a new method, linkage disequilibrium SNP-pair effect correlation regression (LDSPEC), to estimate the correlation of causal disease effect sizes of derived alleles between proximal SNPs; LDSPEC produced robust estimates in simulations. Analyzing 70 UK Biobank diseases and traits (average N = 305,646), we detected significantly non-zero SNP-pair effect correlations (for example, -0.37 ± 0.09 for low-frequency positive linkage disequilibrium 0-100-bp SNP pairs) that decayed with distance and varied with allele frequency and linkage disequilibrium between SNPs. SNP pairs with shared functions had stronger effect correlations that spanned longer genomic distances. Consequently, SNP heritability estimates were smaller than estimates of the sum of causal effect size variances across SNPs, particularly for certain functional annotations. We recapitulated our findings via forward simulations involving stabilizing selection, implicating the action of linkage masking, whereby haplotypes containing linked SNPs with opposite effects on disease have reduced effects on fitness and escape negative selection.

Polymorphism, Single Nucleotide↗
PubMedDate not supplied

Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies.

The 5-HT(2A)-serotonin receptor is a major molecular target for most atypical antipsychotic drugs as well as most hallucinogens, which can exacerbate psychotic symptoms. In this study, we examined whether random sequence variations in the gene (single nucleotide polymorphisms, SNPs) encoding the 5-HT(2A)-serotonin receptor could explain inter-individual variability in atypical antipsychotic and agonist drug response. We examined the in vitro pharmacology of four non-synonymous SNPs, which give rise to T25N, I197V, A447V, and H452Y variant 5-HT(2A)-serotonin receptors. Our data indicate that these non-synonymous SNPs exert statistically significant, although modest, effects on the affinity and functional effects of several currently approved atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone). Also, the 5-HT(2A) receptor SNPs slightly altered the potency and relative efficacy of a small number of selected agonists (2,5-dimethoxy-4-iodoamphetamine, tryptamine, 5-hydroxytryptamine, m-chlorophenylpiperazine, and 5-methoxy-N, N-dimethyltryptamine). In all, our results show that the in vitro pharmacological effects of the SNPs are drug specific.

Antipsychotic Agents↗
PubMedDate not supplied

Haplotype structure of five SNPs within the ACE gene in the Tunisian population.

BACKGROUND: The Angiotensin-Converting Enzyme (ACE) is a candidate gene in the aetiology of several common diseases. The study of the haplotype structure of this gene is of interest in diagnosis and in pharmacogenomics. AIM: The study investigated the haplotype profile of single nucleotide polymorphisms (SNPs) within the ACE gene in the Tunisian population and compared it with other populations. SUBJECTS AND METHODS: Five SNPs (rs1800764, rs4291, rs4309, rs4331, rs4340) covering a region of 15.6 kb of the ACE gene were typed by PCR-digestion in a sample of 100 healthy subjects. RESULTS: All SNPs were polymorphic and in Hardy-Weinberg equilibrium. A total of 21 haplotypes were identified but only eight had a frequency of more than 1%. The four most common haplotypes had a cumulative frequency of 87.4%. The 'Yin-Yang' phenomenon (the two major haplotypes are complementary at all sites) was found. Linkage disequilibrium between all pairs of loci was highly significant (p<10-5). A simple and efficient statistical procedure was used to identify three important SNPs. CONCLUSION: The Tunisian population showed a different haplotype structure from the European one for the ACE gene and three important SNPs were identified. These will be very helpful in future association studies in the Tunisian and North African populations.

Adult↗
PubMed2002

SNPper: retrieval and analysis of human SNPs.

MOTIVATION: Single Nucleotide Polymorphisms (SNPs) are an increasingly important tool for the study of the human genome. SNPs can be used as markers to create high-density genetic maps, as causal candidates for diseases, or to reconstruct the history of our genome. SNP-based studies rely on the availability of large numbers of validated, high-frequency SNPs whose position on the chromosomes is known with precision. Although large collections of SNPs exist in public databases, researchers need tools to effectively retrieve and manipulate them. RESULTS: We describe the implementation and usage of SNPper, a web-based application to automate the tasks of extracting SNPs from public databases, analyzing them and exporting them in formats suitable for subsequent use. Our application is oriented toward the needs of candidate-gene, whole-genome and fine-mapping studies, and provides several flexible ways to present and export the data. The application has been publicly available for over a year, and has received positive user feedback and high usage levels.

Database Management Systems↗
PubMed2005

LS-SNP: large-scale annotation of coding non-synonymous SNPs based on multiple information sources.

MOTIVATION: The NCBI dbSNP database lists over 9 million single nucleotide polymorphisms (SNPs) in the human genome, but currently contains limited annotation information. SNPs that result in amino acid residue changes (nsSNPs) are of critical importance in variation between individuals, including disease and drug sensitivity. RESULTS: We have developed LS-SNP, a genomic scale software pipeline to annotate nsSNPs. LS-SNP comprehensively maps nsSNPs onto protein sequences, functional pathways and comparative protein structure models, and predicts positions where nsSNPs destabilize proteins, interfere with the formation of domain-domain interfaces, have an effect on protein-ligand binding or severely impact human health. It currently annotates 28,043 validated SNPs that produce amino acid residue substitutions in human proteins from the SwissProt/TrEMBL database. Annotations can be viewed via a web interface either in the context of a genomic region or by selecting sets of SNPs, genes, proteins or pathways. These results are useful for identifying candidate functional SNPs within a gene, haplotype or pathway and in probing molecular mechanisms responsible for functional impacts of nsSNPs. AVAILABILITY: http://www.salilab.org/LS-SNP CONTACT: rachelk@salilab.org SUPPLEMENTARY INFORMATION: http://salilab.org/LS-SNP/supp-info.pdf.

Algorithms↗
PubMed2005

SNPselector: a web tool for selecting SNPs for genetic association studies.

SUMMARY: Single nucleotide polymorphisms (SNPs) are commonly used for association studies to find genes responsible for complex genetic diseases. With the recent advance of SNP technology, researchers are able to assay thousands of SNPs in a single experiment. But the process of manually choosing thousands of genotyping SNPs for tens or hundreds of genes is time consuming. We have developed a web-based program, SNPselector, to automate the process. SNPselector takes a list of gene names or a list of genomic regions as input and searches the Ensembl genes or genomic regions for available SNPs. It prioritizes these SNPs on their tagging for linkage disequilibrium, SNP allele frequencies and source, function, regulatory potential and repeat status. SNPselector outputs result in compressed Excel spreadsheet files for review by the user. AVAILABILITY: SNPselector is freely available at http://primer.duhs.duke.edu/

Algorithms↗
PubMed2005

Concordance of multiple analytical approaches demonstrates a complex relationship between DNA repair gene SNPs, smoking and bladder cancer susceptibility.

Study results of single nucleotide polymorphisms (SNPs) and cancer susceptibility are often conflicting, possibly because of the analytic challenges of testing for multiple genetic and environmental risk factors using traditional analytic tools. We investigated the relationship between DNA repair gene SNPs, smoking, and bladder cancer susceptibility in 355 cases and 559 controls enrolled in a population-based study of bladder cancer in the US. Our multifaceted analytical approach included logistic regression, multifactor dimensionality reduction, and hierarchical interaction graphs for the analysis of gene-gene and gene-environment interactions followed by linkage disequilibrium and haplotype analysis. Overall, we did not find an association between any single DNA repair gene SNP and bladder cancer risk. We did find a marginally significant elevated risk of the XPD codon 751 homozygote variant among never smokers [adjusted odds ratio (OR) 2.5, 95% confidence interval (CI) 1.0-6.2]. In addition, the XRCC1 194 variant allele was associated with a reduced bladder cancer risk among heavy smokers [adjusted OR 0.4, 95% CI 0.2-0.9)]. The best predictors of bladder cancer included the XPD codon 751 and 312 SNPs along with smoking. Interpretation of this multifactor model revealed that the relationship between the XPD SNPs and bladder cancer is mostly non-additive while the effect of smoking is mostly additive. Since the two XPD SNPs are in significant linkage disequilibrium (D' = 0.52, P = 0.0001), we estimated XPD haplotypes. Individuals with variant XPD haplotypes were more susceptible to bladder cancer [e.g. adjusted OR 2.5, 95% CI 1.7-3.6] and the effect was magnified when smoking was considered. These results support the hypothesis that common polymorphisms in DNA repair genes modify bladder cancer risk and emphasize the need for a multifaceted statistical approach to identify gene-gene and gene-environment interactions.

Adult↗
PubMed2002

Search for and analysis of single nucleotide polymorphisms (SNPs) in rice (Oryza sativa, Oryza rufipogon) and establishment of SNP markers.

We searched for SNPs in 417 regions distributed throughout the genome of three Oryza sativa ssp. japonica cultivars, two indica cultivars, and a wild rice (O. rufipogon). We found 2800 SNPs in approximately 250,000 aligned bases for an average of one SNP every 89 bp, or one SNP every 232 bp between two randomly selected strains. Graphic representation of the frequency of SNPs along each chromosome showed uneven distribution of polymorphism-rich and -poor regions, but little obvious association with the centromere or telomere. The 94 SNPs that we found between the closely related cultivars 'Nipponbare' and 'Koshihikari' can be converted into molecular markers. Our establishment of 213 co-dominant SNP markers distributed throughout the genome illustrates the immense potential of SNPs as molecular markers not only for genome research, but also for molecular breeding of rice.

Genetic Markers↗
PubMed2005

Discovery of SNPs in soybean genotypes frequently used as the parents of mapping populations in the United States and Korea.

Single nucleotide polymorphisms (SNPs) including insertion/deletions (indels) serve as useful and informative genetic markers. The availability of high-throughput and inexpensive SNP typing systems has increased interest in the development of SNP markers. After fragments of genes were amplified with primers derived from 110 soybean GenBank ESTs, sequencing data of PCR products from 15 soybean genotypes from Korea and the United States were analyzed by SeqScape software to find SNPs. Among 35 gene fragments with at least one SNP among the 15 genotypes, SNPs occurred at a frequency of 1 per 2,038 bp in 16,302 bp of coding sequence and 1 per 191 bp in 16,960 bp of noncoding regions. This corresponds to a nucleotide diversity (theta) of 0.00017 and 0.00186, respectively. Of the 97 SNPs discovered, 78 or 80.4% were present in the six North American soybean mapping parents. The addition of "Hwaeomputkong," which originated from Japan, increased the number to 92, or 94.8% of the total number of SNPs present among the 15 genotypes. Thus, Hwaeomputkong and the six North American mapping parents provide a diverse set of soybean genotypes that can be successfully used for SNP discovery in coding DNA and closely associated introns and untranslated regions.

Base Sequence↗
PubMed2005

Human SNPs reveal no evidence of frequent positive selection.

We compared the single-nucleotide polymorphisms (SNPs) in humans in 182 housekeeping and 148 tissue-specific genes. SNPs were divided into rare and common polymorphisms based on their frequencies. We found that housekeeping genes tend to be less polymorphic than tissue-specific genes for both rare and common SNPs. Using mouse as a second species for computing sequence divergences, we found no evidence of positive selection: for both housekeeping and tissue-specific genes, the ratio of nonsynonymous to synonymous common SNPs per site showed no significant difference from that of divergence. Similarly, we observed no evidence of positive selection for the 289 and 149 genes that have orthologs available for divergence calculation between humans and chimpanzees and between humans and Old World monkeys, respectively. A comparison with previous SNP studies suggests that approximately 20% of the nonsynonymous SNPs in the human population are nearly neutral and that positive selection in the human genome might not be as frequent as previously thought.

Animals↗
PubMed2002

Human non-synonymous SNPs: server and survey.

Human single nucleotide polymorphisms (SNPs) represent the most frequent type of human population DNA variation. One of the main goals of SNP research is to understand the genetics of the human phenotype variation and especially the genetic basis of human complex diseases. Non-synonymous coding SNPs (nsSNPs) comprise a group of SNPs that, together with SNPs in regulatory regions, are believed to have the highest impact on phenotype. Here we present a World Wide Web server to predict the effect of an nsSNP on protein structure and function. The prediction method enabled analysis of the publicly available SNP database HGVbase, which gave rise to a dataset of nsSNPs with predicted functionality. The dataset was further used to compare the effect of various structural and functional characteristics of amino acid substitutions responsible for phenotypic display of nsSNPs. We also studied the dependence of selective pressure on the structural and functional properties of proteins. We found that in our dataset the selection pressure against deleterious SNPs depends on the molecular function of the protein, although it is insensitive to several other protein features considered. The strongest selective pressure was detected for proteins involved in transcription regulation.

Databases, Genetic↗
PubMed2003

Single nucleotide polymorphisms (SNPs) that map to gaps in the human SNP map.

An international effort is underway to generate a comprehensive haplotype map (HapMap) of the human genome represented by an estimated 300,000 to 1 million 'tag' single nucleotide polymorphisms (SNPs). Our analysis indicates that the current human SNP map is not sufficiently dense to support the HapMap project. For example, 24.6% of the genome currently lacks SNPs at the minimal density and spacing that would be required to construct even a conservative tag SNP map containing 300,000 SNPs. In an effort to improve the human SNP map, we identified 140,696 additional SNP candidates using a new bioinformatics pipeline. Over 51,000 of these SNPs mapped to the largest gaps in the human SNP map, leading to significant improvements in these regions. Our SNPs will be immediately useful for the HapMap project, and will allow for the inclusion of many additional genomic intervals in the final HapMap. Nevertheless, our results also indicate that additional SNP discovery projects will be required both to define the haplotype architecture of the human genome and to construct comprehensive tag SNP maps that will be useful for genetic linkage studies in humans.

Base Sequence↗
PubMed2005

SNPeffect: a database mapping molecular phenotypic effects of human non-synonymous coding SNPs.

Single nucleotide polymorphisms (SNPs) are an increasingly important tool for genetic and biomedical research. However, the accumulated sequence information on allelic variation is not matched by an understanding of the effect of SNPs on the functional attributes or 'molecular phenotype' of a protein. Towards this aim we developed SNPeffect, an online resource of human non-synonymous coding SNPs (nsSNPs) mapping phenotypic effects of allelic variation in human genes. SNPeffect contains 31 659 nsSNPs from 12 480 human proteins. The current release of SNPeffect incorporates data on protein stability, integrity of functional sites, protein phosphorylation and glycosylation, subcellular localization, protein turnover rates, protein aggregation, amyloidosis and chaperone interaction. The SNP entries are accessible through both a search and browse interface and are linked to most major biological databases. The data can be displayed as detailed descriptions of individual SNPs or as an overview of all SNPs for a given protein. SNPeffect will be regularly updated and can be accessed at http://snpeffect.vib.be/.

Alleles↗
PubMed2001

A SNP resource for human chromosome 22: extracting dense clusters of SNPs from the genomic sequence.

The recent publication of the complete sequence of human chromosome 22 provides a platform from which to investigate genomic sequence variation. We report the identification and characterization of 12,267 potential variants (SNPs and other small insertions/deletions) of human chromosome 22, discovered in the overlaps of 460 clones used for the chromosome sequencing. We found, on average, 1 potential variant every 1.07 kb and approximately 18% of the potential variants involve insertions/deletions. The SNPs have been positioned both relative to each other, and to genes, predicted genes, repeat sequences, other genetic markers, and the 2730 SNPs previously identified on the chromosome. A subset of the SNPs were verified experimentally using either PCR-RFLP or genomic Invader assays. These experiments confirmed 92% of the potential variants in a panel of 92 individuals. [Details of the SNPs and RFLP assays can be found at http://www.sanger.ac.uk and in dbSNP.]

Base Composition↗
PubMed2005

Genetically indistinguishable SNPs and their influence on inferring the location of disease-associated variants.

As part of a recent high-density linkage disequilibrium (LD) study of chromosome 20, we obtained genotypes for approximately 30,000 SNPs at a density of 1 SNP/2 kb on four different population samples (47 CEPH founders; 91 UK unrelateds [unrelated white individuals of western European ancestry]; 97 African Americans; 42 East Asians). We observed that approximately 50% of SNPs had at least one genetically indistinguishable partner; i.e., for every individual considered, their genotype at the first locus was identical to their genotype at the second locus, or in LD terms, the SNPs were in "perfect" LD (r2 = 1.0). These "genetically indistinguishable SNPs" (giSNPs) formed into clusters of varying size. The larger the cluster, the greater the tendency to be located within genes and to overlap with giSNP clusters in other population samples. As might be expected for this map density, many giSNPs were located close to one another, thus reflecting local regions of undetected recombination or haplotype blocks. However, approximately 1/3 of giSNP clusters had intermingled, non-indistinguishable SNPs with incomplete LD (D' and r2 <1), sometimes spanning hundreds of kilobases, comprising up to 70 indistinguishable markers and overlapping multiple haplotype blocks. These long-range, nonconsecutive giSNPs have implications for disease gene localization by allelic association as evidence for association at one locus will be indistinguishable from that at another locus, even though both loci may be situated far apart. We describe the distribution of giSNPs on this map of chromosome 20 and illustrate the potential impact they can have on association mapping.

Black or African American↗
PubMed2026

Comparisons Between Large-Scale Genomic Variants and SNPs in Driving Population Divergence and Local Adaptation.

Genomic variations, such as indels (2-49 bp) and structural variants (SVs, &#x2265;50 bp), are larger-scale mutations than single nucleotide polymorphisms (SNPs) and can substantially impact evolutionary processes, including speciation, adaptation, and phenotypes. Despite their functional importance, integrative population genetic analyses that jointly consider genome-wide SNPs, indels, and SVs remain under-explored. The ground tit (Pseudopodoces humilis), an endemic species to the Qinghai-Tibet Plateau (QTP), exhibits divergence across distinct glacial refugia, accompanied by habitat and morphological divergence, making it an excellent example for investigating how different types of genomic variants contribute to population divergence and local adaptation. Here, by retrieving 81 whole-genome sequence data, over 13 million SNPs, 2 million indels, and 22,101 SVs were identified. Variants were unevenly distributed across the genome, characterized by distinct hotspot regions. Indels and SVs revealed four genetic clusters consistent with previous SNP-based results, thereby validating the reliability of our variant datasets. FST and genotype-environment association (GEA) analyses independently revealed numerous candidate indels and SVs; each showed minimal overlap with previously identified SNPs, and were enriched in similar functional pathways such as signal transduction, skeletal muscle development, water transport, DNA repair, reproduction, nervous system development, and immunity. Collectively, our results demonstrated that indels and SVs could capture additional signatures besides SNPs. Furthermore, similar but distinct gene functions among different types of genomic variants collectively and complementarily drive genomic divergence across environmental gradients in such a high-elevation endemic species, underscoring its evolutionary relevance in local adaptation.

indels↗
PubMed2005

TNFalpha and IL10 SNPs act together to predict disease behaviour in Crohn's disease.

BACKGROUND: The cytokines tumour necrosis factor (TNF)alpha and interleukin (IL)10 have been implicated in the pathogenesis of Crohn's disease (CD), with increased concentrations reported in patients with active disease. However, limited data exist on their effects on disease phenotype in the same population. Certain single nucleotide polymorphisms (SNPs) within the promoter region of the IL10 (-1082G/A, -592C/A) and TNFalpha (-308G/A, -857C/T) genes have been associated with altered levels of circulating IL10 and TNFalpha. METHODS: We conducted an Australian based case-control study (304 CD patients; 231 healthy controls) of these four SNPs. Further investigation of two SNPs was conducted using a logistic regression analysis. RESULTS: We identified a possible association of both IL10 SNPs and TNFalpha-857 with CD. Further investigation of a relationship with disease severity showed a significant association of higher producing IL10-1082G and TNFalpha-857C alleles with stricturing behaviour, which was strongest when these alleles were combined and persisted after multivariate analysis (p = 0.007; odds ratio (OR) 2.37, 95% CI 1.26 to 4.43). In addition, the TNFalpha-857CC genotype was independently associated with familial CD (p = 0.03; OR 3.12; 95% CI 1.15 to 8.46). CONCLUSION: These two SNPs may help to predict disease behaviour in CD patients, which may be clinically useful in shaping treatment of the disease at an earlier stage.

Adult↗
PubMed2003

Number of SNPS loci needed to detect population structure.

The study of the association of polymorphic genetic markers with common diseases is one of the most powerful tools in modern genetics. Interest in single nucleotide polymorphisms (SNPs) has steadily grown over the last decade. SNPs are currently the most developed markers in the human genome because they have a number of advantages over other marker types. One of the critical problems responsible for 'spurious' association findings in case-control studies is population stratification. There are many statistical approaches developed for detecting population heterogeneity. However the power to detect population structure by known methods is highly dependent on the number of loci utilised. We performed an analysis of SNPs data available in the public domain from The Single Nucleotide Consortia Ltd. (TSCL). Three populations, Afro-American, Asian and Caucasian, were compared. Estimation of the minimum number of SNPs loci necessary for detection of the population structure was performed. Two clustering approaches, distance-based and model-based, were compared. The model-based approach was superior when compared with the distance-based method. We found more than 65 random SNPs loci are required for identifying distinct geographically separated populations. Increasing the number of markers to over 100 raises the probability of correct assignment of a particular individual to an origin group to over 90%, even with conventional clustering methods.

Genetic Markers↗