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PubMed2005

Inference of human geographic origins using Alu insertion polymorphisms.

The inference of an individual's geographic ancestry or origin can be critical in narrowing the field of potential suspects in a criminal investigation. Most current technologies rely on single nucleotide polymorphism (SNP) genotypes to accomplish this task. However, SNPs can introduce homoplasy into an analysis since they can be identical-by-state. We introduce the use of insertion polymorphisms based on short interspersed elements (SINEs) as a potential alternative to SNPs. SINE polymorphisms are identical-by-descent, essentially homoplasy-free, and inexpensive to genotype using a variety of approaches. Herein, we present results of a blind study using 100 Alu insertion polymorphisms to infer the geographic ancestry of 18 unknown individuals from a variety of geographic locations. Using a Structure analysis of the Alu insertion polymorphism-based genotypes, we were able to correctly infer the geographic affiliation of all 18 unknown human individuals with high levels of confidence. This technique to infer the geographic affiliation of unknown human DNA samples will be a useful tool in forensic genomics.

Alu Elements↗
PubMed2006

Association of the gene encoding neurogranin with schizophrenia in males.

The neurogranin (NRGN) gene produces a postsynaptic brain-specific protein that regulates calmodulin-Ca(2+) availability in neurons. Acting downstream of the NMDA receptor and upstream of calcineurin and other proteins implicated in schizophrenia, NRGN is a good candidate for association studies in schizophrenia. NRGN expression is regulated during development and is modulated by thyroid hormones and retinoids, molecules essential for the proper development of the central nervous system. Given the genetic complexity of schizophrenia and the potential genetic heterogeneity in different populations, we studied a possible association of NRGN with schizophrenia in 73 Azorean proband-parent triads and in two independent case-control samples from the Portuguese-mainland (244 schizophrenic and 210 controls) and Brazil (69 schizophrenic and 85 mentally healthy individuals). Genotype distribution showed association of the rs7113041 SNP with schizophrenia in males of Portuguese origin, which was confirmed by the analysis of the proband-parent triads. This evidence, implicating NRGN in schizophrenia, introduces another player into the glutamatergic hypothesis of schizophrenia.

Age of Onset↗
PubMed2003

Analysis of genetic variations of protein tyrosine kinase fyn and their association with alcohol dependence in two independent cohorts.

BACKGROUND: Decreased sensitivity to and increased tolerance for the effects of alcohol is a phenotype, which was shown to be associated with an increased risk for alcoholism in humans and was observed in protein tyrosine kinase (PTK) fyn knockout mice. METHODS: We performed an association study of genetic variations of PTK fyn in 430 alcohol-dependent patients and 365 unrelated control subjects from two independent samples. RESULTS: In a combined analysis, we found an association of alcohol dependence with the single nucleotide polymorphism (SNP) T137346C in the 5' untranslated region (UTR) of the gene. A relevant association could be excluded for the remaining two informative SNPs. Selection by phenotype showed that a high number of withdrawal symptoms, high amount of alcohol intake, and high maximum number of drinks compared with unrelated control subjects was associated with the SNP in the 5'-UTR region but not with the remaining SNPs. CONCLUSIONS: Our results indicate a possible association of alcohol dependence with a genotype of the SNP T137346C of the PTK fyn, with C being the risk allele.

5' Untranslated Regions↗
PubMed2002

Multiplexed, high-throughput genotyping by single-base extension and end-labeled free-solution electrophoresis.

Technologies that allow for high-throughput, economical, and accurate single nucleotide polymorphism (SNP) genotyping are becoming crucial for modern genomic efforts. Here, we present a method for multiplexed single-base extension (SBE) genotyping that takes advantage of the unique separation modalities made possible via end-labeled free-solution electrophoresis (ELFSE). Three unique SBE oligonucleotide primers, which probe for mutations of clinical importance in the human p53 gene, were covalently conjugated to three unique polypeptoid frictional end labels and mixed together. This primer-polypeptoid conjugate cocktail was then used in a multiplexed SBE reaction followed by free-solution separation in a 96-capillary array electrophoresis (CAE) instrument. The study was designed to demonstrate multiplexed SNP genotyping of several loci in a single reaction and a single subsequent analysis. Further, the electrophoretic analysis was conducted without any viscous polymeric separation media, was complete in less than 10 min, and can be implemented in any capillary or microfluidic electrophoretic system with four-color fluorescent detection capabilities. Multiplexed SBE-ELFSE genotyping analysis resulted in the simultaneous and accurate genotyping of three p53 loci on five different DNA templates in a single reaction set and single CAE analysis. With the implementation of this method in 96 or more capillaries in parallel, high-throughput screening of SNPs will be accessible to a large number of laboratories.

DNA Primers↗
PubMed2001

Sex, genes and blood pressure.

1. Throughout most of life, males have higher average blood pressures than females. This sexual dichotomy may be related to genetic factors including the X and Y sex chromosomes and genes that control sex steroids. Resultant physiological differences between men and women may also be relevant to the quantitative variation of blood pressure within the sexes. 2. The present overview collates our published and novel sex-related genetic data in relation to blood pressure from the Victorian Family Heart Study. These include a multipoint quantitative linkage analysis of the X chromosome and genetic association studies of single nucleotide polymorphisms (SNP) of the Y chromosome and genes encoding the androgen receptor (AR), oestrogen receptor alpha (ERalpha), 5alpha-reductase types I and II (SRD5A1 and SRD5A2) and aromatase (CYP19). 3. Systolic blood pressure (SBP) was linked (Z=3.3, genome-wide P < 0.05) to a region of the X chromosome that encompassed the AR gene and the Y chromosome was associated with diastolic blood pressure (DBP; P=0.03). In new analyses, we observed a possible association between a SNP in AR and DBP in 369 males (84.5 vs 82.1 mmHg for genotype A vs genotype B, respectively; P=0.06) and a significant association between haplotypes of the Y chromosome and AR SNP in males (P=0.01) with a difference of nearly 6 mmHg DBP between extreme groups. Associations were also observed for polymorphisms of SRD5A1 and ERalpha with DBP and SBP in males, respectively. 4. The findings indicate that genes related to sexual phenotypes may be relevant to the normal variation in blood pressure, even within the sexes. Further genetic and physiological analyses will be required to confirm these observations and to determine the mechanisms of action and the nature of any interactions.

Adolescent↗
PubMed2000

Haplotypes at ATM identify coding-sequence variation and indicate a region of extensive linkage disequilibrium.

Genetic variation in the human population may lead to functional variants of genes that contribute to risk for common chronic diseases such as cancer. In an effort to detect such possible predisposing variants, we constructed haplotypes for a candidate gene and tested their efficacy in association studies. We developed haplotypes consisting of 14 biallelic neutral-sequence variants that span 142 kb of the ATM locus. ATM is the gene responsible for the autosomal recessive disease ataxia-telangiectasia (AT). These ATM noncoding single-nucleotide polymorphisms (SNPs) were genotyped in nine CEPH families (89 individuals) and in 260 DNA samples from four different ethnic origins. Analysis of these data with an expectation-maximization algorithm revealed 22 haplotypes at this locus, with three major haplotypes having frequencies > or = .10. Tests for recombination and linkage disequilibrium (LD) show reduced recombination and extensive LD at the ATM locus, in all four ethnic groups studied. The most striking example was found in the study population of European ancestry, in which no evidence for recombination could be discerned. The potential of ATM haplotypes for detection of genetic variants through association studies was tested by analysis of 84 individuals carrying one of three ATM coding SNPs. Each coding SNP was detected by association with an ATM haplotype. We demonstrate that association studies with haplotypes for candidate genes have significant potential for the detection of genetic backgrounds that contribute to disease.

Algorithms↗
PubMed2003

An exponential dispersion model for the distribution of human single nucleotide polymorphisms.

An analysis of 1.42 million human single nucleotide polymorphisms (SNPs), mapped by the International SNP Map Working Group, revealed an apparent power function relationship between the estimated variance and mean number of SNPs per sample bin. This relationship could be explained by the assumption that a scale invariant Poisson gamma (PG) exponential dispersion model could describe the distribution of SNPs within the bins. In this model the sample bins would contain random (Poisson distributed) numbers of identical by descent genomic segments, each with independently distributed and gamma distributed numbers of SNPs. This model was both qualitatively and quantitatively consistent with the conventional coalescent model. It agreed with the empirical cumulative distribution functions derived from the SNP maps as well as with simulated data. The model was used to estimate the heterozygosity pi, and the mean number and size of haplotype blocks for each chromosome. These estimates were consistent with measurements from conventional studies. This PG model thus provides an alternative to Monte Carlo simulation for description of the distribution of SNPs.

Computer Simulation↗
PubMed2004

CpG mutation rates in the human genome are highly dependent on local GC content.

CpG dinucleotides mutate at a high rate because cytosine is vulnerable to deamination, cytosines in CpG dinucleotides are often methylated, and deamination of 5-methylcytosine (5mC) produces thymidine. Previous experiments have shown that DNA melting is the rate-limiting step in cytosine deamination. Here we show, through the analysis of human single-nucleotide polymorphisms (SNPs), that the mutation rate produced by 5mC deamination is highly dependent on local GC content. In fact, linear regression analysis showed that the log(10) of the 5mC mutation rates (inferred from SNP frequencies) had slopes of -3 when graphed with respect to the GC content of neighboring sequences. This is the ideal slope that would be expected if the correlation between CpG underrepresentation and GC content had been solely caused by DNA melting. Moreover, this same result was obtained regardless of the SNP locations (all SNPs versus only SNPs in noncoding intergenic regions, excluding CpG islands) and regardless of the lengths over which GC content was calculated (SNP sequences with a modal length of 564 bp versus genomic contigs with a modal length of 163 kb). Several alternative interpretations are discussed.

Animals↗
PubMed2002

Novel approach for SNP genotyping based on site-selective RNA scission.

Novel genotyping method for single nucleotide polymorphisms (SNPs), based on site-selective RNA scission, has been developed. A substrate RNA is activated at two sites by complementary acridine-modified DNA having two acridine residues, and is site-selectively cleaved by metal ion catalyst to produce short RNA fragment containing the SNP site. Genotype of the substrate is accurately and easily determined by mass analysis of the fragment.

Base Sequence↗
PubMed2006

Micro-phylogeographic and demographic history of Portuguese male lineages.

The clinal pattern observed for the distribution of Y-chromosome lineages in Europe is not always reflected at a geographically smaller scale. Six hundred and sixty-three male samples from the 18 administrative districts of Portugal were typed for 25 Y-chromosome biallelic and 15 microsatellite markers, in order to assess the degree of substructuring of male lineage distribution. Haplogroup frequency distributions, Analysis of Molecular Variance (AMOVA) and genetic distance analyses at both Y-SNP and Y-STR levels revealed a general genetic homogeneity of Portuguese sub-populations. The traditional division of the country in north, central and south, which is usually considered in studies addressing questions of the genetic variation distribution in Portugal, was not reflected in the Y-haplotype distribution. Instead, just one sub-region (Alentejo) stood out due to the presence of high diversity levels and a higher number of different lineages, at higher frequencies than in other regions. These results are reconciled with the historical evidence available, assuming that from prehistorical times down to the end of the medieval period this region harboured the most diverse groups of people and, because of economic depression, remained relatively isolated from recent homogenisation movements. The finding of a broadly homogeneous background for the Portuguese population has vast repercussions in forensic, epidemiological and association studies.

Chromosomes, Human, Y↗
PubMed2007

A case-control investigation of immune function gene polymorphisms and risk of testicular germ cell tumors.

There is reason to suspect that testicular germ cell tumor (TGCT) development may be influenced by cytokines, secreted proteins that modulate tumor immune surveillance activity as well as a variety of processes in the testis. To address this hypothesis, we conducted a case-control analysis (508 cases, 608 controls) of 32 putatively functional single-nucleotide polymorphisms (SNP) in 16 immune function genes among non-Hispanic Caucasian participants in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study. The TGFB1 Ex5-73C>T variant was positively associated with TGCT (CT/TT versus CC: odds ratio, 1.73; 95% confidence interval, 1.01-2.95; P(trend) = 0.05); additionally, haplotypes of the assessed TGFB1 SNPs (-509C>T, 327C>T, Ex1-282C>G, and Ex5-73C>T) differed in frequency between cases and controls (all TGCT, P 0.07; seminoma, P 0.04; nonseminoma, P 0.11). We also observed excess frequencies among TGCT cases versus controls of LTA 252G (P(trend) = 0.08) and of the TNF variants -1042C (P(trend) = 0.06), -1036T (P(trend) = 0.07), and -238G (P(trend) = 0.09). Analyses of haplotypes for LTA-TNF SNPs (LTA -91C>A, LTA 252A>G, TNF -863C>A, TNF -857C>T, TNF -308G>A, and -238G>A) were similarly suggestive of an association with TGCT (P = 0.06) and nonseminoma (P = 0.04), but not seminoma (P = 0.21). Polymorphisms in other genes were found to be associated only with seminoma (IL2) or nonseminoma (IFNGR2 and IL10). However, none of the associations remained noteworthy after applying the false discovery rate method to control for multiple testing. In conclusion, our findings suggest that polymorphisms in TGFB1 and LTA/TNF, and possibly other immune function genes, may influence susceptibility to TGCT.

Case-Control Studies↗
PubMed2006

SNPs and interaction analyses of noelin 2, myocilin, and optineurin genes in Japanese patients with open-angle glaucoma.

PURPOSE: To evaluate the noelin 2 gene as a disease-causing factor for open-angle glaucoma (OAG) and the interactions between the noelin 2 (OLFM2), optineurin (OPTN), and myocilin (MYOC) genes. METHODS: OLFM2 was analyzed in 770 Japanese subjects including 215 patients with elevated intraocular pressure (IOP), 277 with normal IOP, 38 with juvenile open-angle glaucoma, and 240 control subjects. Two single-nucleotide polymorphisms (SNPs) in OPTN (c.412G-->A and c.603T-->A) and one SNP in MYOC (c.227G-->A) were examined. Single genes were investigated by univariate analysis and the gene-gene interactions by logistic regression analysis. Associations between genotypes and clinical characteristics at the time of diagnosis were examined. RESULTS: In OLFM2, 12 sequence variants were identified in 770 Japanese subjects. Arg144Gln (exon 4) was identified in two (0.3%) of the patients and in none of the control subjects. Combinations of OLFM2/317A and OPTN/412A or OLFM2/1281T and OPTN/412A were associated with patients with elevated IOP (P = 0.018 or P = 0.012, respectively). The combination of OLFM2/317G and OPTN/603A was significantly associated with elevated IOP (P = 0.018). No significant association was detected between SNPs in OLFM2 and in MYOC. Patients with normal IOP and with OLFM2/678A+OPTN/412G or OLFM2/1281C+OPTN/412G had significantly worse visual field scores (P = 0.022 or 0.030, respectively). CONCLUSIONS: The Arg144Gln mutation in OLFM2 is a possible disease-causing mutation in Japanese patients with OAG. Common polymorphisms in OLFM2 and OPTN may interactively contribute to the development of OAG, indicating a polygenic etiology.

Adult↗
PubMed2005

Single nucleotide polymorphisms in the interleukin-6 gene associated with blood pressure and atherosclerosis in a Japanese general population.

It is known that increased plasma levels of inflammatory markers, such as interleukin-6 (IL-6), are associated with atherosclerosis and myocardial infarction. The aim of this study was to reveal the contribution of the single nucleotide polymorphisms (SNPs) of the IL-6 gene on the blood pressure regulation and progression of atherosclerosis in a general Japanese population. In order to evaluate the potential implications of genetic variability of the IL-6 gene, we explored eight SNPs by direct sequencing for the entire coding region and the promoter region in the IL-6 gene and genotyped two SNPs, -636G > C in the promoter region and 1691C > G in intron 3, for a total of 2,421 Japanese subjects (1,162 men and 1,259 women). As a consequence, -636 G > C was significantly associated with systolic blood pressure (SBP) and carotid intima-media thickness (IMT) in women, and 1691C > G showed a relationship with SBP and carotid IMT in men after adjustment for all confounding factors. Although neither SNP had a significant correlation to the prevalence of hypertension, the haplotype frequency analysis indicated that the number of hypertensive men with a G allele at both -636 and 1691 was significantly greater than the number of nonhypertensive men with this combination. Thus, these two SNPs in the promoter region and intron 3 of the IL-6 gene might play a role in the blood pressure regulation and progression of atherosclerosis in the Japanese.

Aged↗
PubMed2002

SNPs on human chromosomes 21 and 22 -- analysis in terms of protein features and pseudogenes.

SNPs are useful for genome-wide mapping and the study of disease genes. Previous studies have focused on SNPs in specific genes or SNPs pooled from a variety of different sources. Here, a systematic approach to the analysis of SNPs in relation to various features on a genome-wide scale, with emphasis on protein features and pseudogenes, is presented. We have performed a comprehensive analysis of 39,408 SNPs on human chromosomes 21 and 22 from the SNP consortium (TSC) database, where SNPs are obtained by random sequencing using consistent and uniform methods. Our study indicates that the occurrence of SNPs is lowest in exons and higher in repeats, introns and pseudogenes. Moreover, in comparing genes and pseudogenes, we find that the SNP density is higher in pseudogenes and the ratio of nonsynonymous to synonymous changes is also much higher. These observations may be explained by the increased rate of SNP accumulation in pseudogenes, which presumably are not under selective pressure. We have also performed secondary structure prediction on all coding regions and found that there is no preferential distribution of SNPs in a -helices, b -sheets or coils. This could imply that protein structures, in general, can tolerate a wide degree of substitutions. Tables relating to our results are available from http://genecensus.org/pseudogene.

Algorithms↗
PubMed2006

Visualizing gene determinants of disease in drug discovery.

Target discovery, subphenotype detection and the detection of human heterogeneity are major challenges in drug discovery and development on which genetic markers can have an impact. Visualizing gene determinants of traits in case-control study individuals during drug discovery using contrasts of empirically-derived log Bayes factors (LBFs) from whole-genome scan single nucleotide polymorphism (SNP) data is presented to aid this. Examples of the use of eigen analysis, covariate overlays and individualized aggregation to ontologies are included from disease research studies. Displays of individuals, or exposures of biological features of interest, can encompass unlimited numbers of markers in a single multivariate analysis without multiple testing. This filtering approach is aimed at nonspecialists who find themselves asked to undertake work such as that performed by the authors.

Animals↗
PubMed2006

Assessment of the role of common genetic variation in the transient neonatal diabetes mellitus (TNDM) region in type 2 diabetes: a comparative genomic and tagging single nucleotide polymorphism approach.

Recent evidence supports the strong overlap between genes implicated in monogenic diabetes and susceptibility to type 2 diabetes. Transient neonatal diabetes mellitus (TNDM) is a rare disorder associated with overexpression of genes at a paternally expressed imprinted locus on chromosome 6q24. There are two overlapping genes in this region: the transcription factor zinc finger protein associated with cell cycle control and apoptosis (ZAC also known as PLAGL1) and HYMA1, which encodes an untranslated mRNA. Several type 2 diabetes linkage studies have reported linkage to chromosome 6q22-25. We hypothesized that common genetic variation at this TNDM region influences type 2 diabetes susceptibility. In addition to the coding regions, we used comparative genomic analysis to identify conserved noncoding regions, which were resequenced for single nucleotide polymorphism (SNP) discovery in 47 individuals. Twenty-six SNPs were identified. Fifteen tag SNPs (tSNPs) were successfully genotyped in a large case-control (n = 3,594) and family-based (n = 1,654) study. We did not find any evidence of association or overtransmission of any tSNP to affected offspring or of a parent-of-origin effect. Using a study sufficiently powered to detect odds ratios of <1.2, we conclude that common variation in the TNDM region does not play an important role in the genetic susceptibility to type 2 diabetes.

Alleles↗
PubMed2007

Screening of 134 single nucleotide polymorphisms (SNPs) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes.

More than 120 published reports have described associations between single nucleotide polymorphisms (SNPs) and type 2 diabetes. However, multiple studies of the same variant have often been discordant. From a literature search, we identified previously reported type 2 diabetes-associated SNPs. We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium (r(2) > 0.8) with another typed SNP. Of the 114 SNPs examined, we followed up the 20 most significant SNPs (P < 0.10) on an additional 384 case subjects and 366 control subjects from a population-based study in Finland. In the combined data, we replicated association (P < 0.05) for 12 SNPs: PPARG Pro12Ala and His447, KCNJ11 Glu23Lys and rs5210, TNF -857, SLC2A2 Ile110Thr, HNF1A/TCF1 rs2701175 and GE117881_360, PCK1 -232, NEUROD1 Thr45Ala, IL6 -598, and ENPP1 Lys121Gln. The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association (P = 0.012). We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample (P = 0.03), although we also replicated 4 of 58 SNPs from genes that had only one previous report of association.

Aged↗
PubMed2004

[Searching genetic risk factors for sporadic Parkinson's disease].

Multiple genetic and environmental factors are thought to cause idiopathic Parkinson's disease (PD). To identify the genetic factors, we are carrying case-control association studies by genome-wide MS (microsatellite) markers and SNP (single nucleotide polymorphism) markers on the candidate genes, and sib-pair analysis. We investigated 27,000 MS markers and found 8% of them were significantly associated with PD in the first screening. In the candidate gene approach, of 267 SNPs on 122 candidate genes, 22 SNPs on 16 genes showed significant p-values (less than 0.05) by chi-square statistics. The further analysis is necessary to identify causative genes for PD.

Humans↗