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PubMed2005

Genome-wide linkage analysis for alcohol dependence: a comparison between single-nucleotide polymorphism and microsatellite marker assays.

Both theoretical and applied studies have proven that the utility of single nucleotide polymorphism (SNP) markers in linkage analysis is more powerful and cost-effective than current microsatellite marker assays. Here we performed a whole-genome scan on 115 White, non-Hispanic families segregating for alcohol dependence, using one 10.3-cM microsatellite marker set and two SNP data sets (0.33-cM, 0.78-cM spacing). Two definitions of alcohol dependence (ALDX1 and ALDX2) were used. Our multipoint nonparametric linkage analysis found alcoholism was nominal linked to 12 genomic regions. The linkage peaks obtained by using the microsatellite marker set and the two SNP sets had a high degree of correspondence in general, but the microsatellite marker set was insufficient to detect some nominal linkage peaks. The presence of linkage disequilibrium between markers did not significantly affect the results. Across the entire genome, SNP datasets had a much higher average linkage information content (0.33 cM: 0.93, 0.78 cM: 0.91) than did microsatellite marker set (0.57). The linkage peaks obtained through two SNP datasets were very similar with some minor differences. We conclude that genome-wide linkage analysis by using approximately 5,000 SNP markers evenly distributed across the human genome is sufficient and might be more powerful than current 10-cM microsatellite marker assays.

Alcoholism↗

PubMed2003

Connexin 26 35delG does not represent a mutational hotspot.

Non-syndromic hearing impairment (NSHI) is the most common form of deafness and presents with no other symptoms or sensory defects. Mutations in the gap junction gene GJB2 account for a high proportion of recessive NSHI. The GJB2 gene encodes connexin 26, which forms plasma membrane channels between cochlear cells. In Caucasian populations a single mutation, 35delG, accounts for most cases of NSHI. This mutation appears to be most prevalent in individuals of Mediterranean European descent, with carrier frequencies estimated as being as high as one in thirty. The 35delG region may be a mutational hotspot. The mutation arises from the deletion of a guanine from a six-guanine stretch and nearby microsatellite markers show little evidence for linkage disequilibrium. We believe that 35delG is an old mutation in a chromosomal region of high recombination. The genetic context of the 35delG mutation was examined to distinguish between an old or a recurring mutation. We identified two single-nucleotide polymorphisms (SNPs) immediately upstream of the first exon of GJB2. Polymerase chain reaction/restriction fragment length polymorphism analysis determined the SNP genotype of 35delG containing chromosomes from various populations, including Italy, Brazil, and North America. We found the same, relatively rare, polymorphism associated with the 35delG mutation in all populations studied. We have also examined microsatellite markers D13S175, which is 80 kb telomeric to GJB2, and D13S1316, which is 80 kb centromeric to GJB2. D13S175 appears to be in weak linkage disequilibrium with 35delG, while D13S1316 is less so. SNPs located between the 35delG mutation and the microsatellite markers show strong evidence of linkage disequilibrium. Taken together, these results indicate there has been substantial recombination near the 35delG mutation; however, we present evidence that the 35delG mutation arose in European and Middle Eastern populations from a single mutational event on a founder chromosome.

Alleles↗

PubMed2003

Homogeneous real-time detection of single-nucleotide polymorphisms by strand displacement amplification on the BD ProbeTec ET system.

BACKGROUND: The BD ProbeTec ET System is based on isothermal strand displacement amplification (SDA) of target nucleic acid coupled with homogeneous real-time detection using fluorescent probes. We have developed a novel, rapid method using this platform that incorporates a universal detection format for identification of single-nucleotide polymorphisms (SNPs) and other genotypic variations. METHOD: The system uses a common pair of fluorescent Detector Probes in conjunction with unlabeled allele-specific Adapter Primers and a universal buffer chemistry to permit analysis of multiple SNP loci under generic assay conditions. We used Detector Probes labeled with different dyes to facilitate differentiation of two alternative alleles in a single reaction with no postamplification manipulation. We analyzed six SNPs within the human beta(2)-adrenergic receptor (beta(2)AR) gene, using whole blood, buccal swabs, and urine samples, and compared results with those obtained by DNA sequencing. RESULTS: Unprocessed whole blood was successfully genotyped with as little as 0.1-1 micro L of sample per reaction. All six beta(2)AR assays were able to accommodate >/==" BORDER="0">20 micro L of unprocessed whole blood. For the 14 individuals tested, genotypes determined with the six beta(2)AR assays agreed with DNA sequencing results. CONCLUSION: SDA-based allelic differentiation on the BD ProbeTec ET System can detect SNPs rapidly, using whole blood, buccal swabs, or urine.

Alleles↗

PubMed2007

High-resolution analysis of allelic imbalance in neuroblastoma cell lines by single nucleotide polymorphism arrays.

Genomic copy number changes are detectable in many malignancies, including neuroblastoma, using techniques such as comparative genomic hybridization (CGH), microsatellite analysis, conventional karyotyping, and fluorescence in situ hybridization (FISH). We report the use of 10K single nucleotide polymorphism (SNP) microarrays to detect copy number changes and allelic imbalance in six neuroblastoma cell lines (IMR32, SHEP, NBL-S, SJNB-1, LS, and SKNBE2c). SNP data were generated using the GeneChip DNA Analysis and GeneChip chromosome copy number software (Affymetrix). SNP arrays confirmed the presence of all previously reported cytogenetic abnormalities in the cell lines, including chromosome 1p deletion, MYCN amplification, gain of 17q and 11q, and 14q deletions. In addition, the SNP arrays revealed several chromosome gains and losses not detected by CGH or karyotyping; these included gain of 8q21.1 approximately 24.3 and gain of chromosome 12 in IMR-32 cells; loss at 4p15.3 approximately 16.1 and loss at 16p12.3 approximately 13.2, 11q loss with loss of heterozygosity (LOH) at 11q14.3 approximately 23.3 in SJNB-1 cells; and loss at 8p21.2 approximately 23.3 and 9p21.3 approximately 22.1 with corresponding LOH in SHEP cells. The SNP arrays refined the mapping of the 2p amplicons in LS, BE2c, and IMR-32 cell lines, the 12q amplicon in LS cells, and also identified an 11q13 amplicon in LS cells. There was good concordance among SNP arrays, CGH, and karyotyping. SNP array analysis is a powerful tool for the detection of allelic imbalance in neuroblastoma and also allows identification of LOH without changes in copy number (uniparental disomy).

Allelic Imbalance↗

PubMed2002

Predicting the success of primer extension genotyping assays using statistical modeling.

Using an empirical panel of more than 20 000 single base primer extension (SNP-IT) assays we have developed a set of statistical scores for evaluating and rank ordering various parameters of the SNP-IT reaction to facilitate high-throughput assay primer design with improved likelihood of success. Each score predicts either signal magnitude from primer extension or signal noise caused by mispriming of primers and structure of the PCR product. All scores have been shown to correlate with the success/failure rate of the SNP-IT reaction, based on analysis of assay results. A logistic regression analysis was applied to combine all scored parameters into one measure predicting the overall success/failure rate of a given SNP marker. Three training sets for different types of SNP-IT reaction, each containing about 22 000 SNP markers, were used to assign weights to each score and optimize the prediction of the combined measure. c-Statistics of 0.69, 0.77 and 0.72 were achieved for three training sets. This new statistical prediction can be used to improve primer design for the SNP-IT reaction and evaluate the probability of genotyping success for a given SNP based on analysis of the surrounding genomic sequence.

DNA Primers↗

PubMed2026

Spatial clustering and transmission networks of multidrug-resistant tuberculosis in Rwanda: a national retrospective genomic and spatial epidemiological study.

BACKGROUND: Approximately 96% of rifampicin resistance/multidrug-resistant tuberculosis (RR/MDR-TB) cases in Rwanda result from direct transmission rather than acquired resistance. However, the nationwide spatial distribution and transmission dynamics of RR/MDR-TB remain poorly characterised. This study aims to analyse spatial patterns of RR/MDR-TB in Rwanda and explore relationships between spatial proximity and RR/MDR-TB strains' genetic relatedness. METHODS: We conducted a retrospective analysis of 249 confirmed RR-TB cases across Rwanda from 2017 to 2024, using the known geolocations of patients' residences. Spatial and space-time clustering was assessed using Kulldorff's scan statistics. Demographic and socioeconomic determinants were evaluated using multivariable regression. For 201 cases with whole-genome sequencing data, we performed transmission analysis using a 5-SNP threshold to define recent transmission clusters and investigated spatial relationships within genetically related strains. RESULTS: Significant spatial clustering of RR/MDR-TB was identified in 21 sectors, mainly in Nyarugenge, southern Gasabo and western Kicukiro (relative risk: 10.06; p<0.001). Our multivariable analysis showed that population density is positively associated with case notification rates. Molecular analysis revealed 88.5% of cases belonged to genotype clusters defined using a 12-SNP threshold, with 73.6% forming clusters at a strict 5-SNP threshold. Spatial K-function analysis of the six major clusters revealed heterogeneous transmission patterns, characterised by both tightly clustered outbreaks and regional transmission networks that spanned administrative boundaries. Most clusters (5/6) extended beyond Kigali, indicating that transmission networks operate across administrative divides. CONCLUSION: RR/MDR-TB in Rwanda shows significant spatial clustering with transmission occurring through both localised and regional networks. Integrating genomic and spatial data reveals transmission patterns that extend beyond household contacts and administrative boundaries. These findings underscore the need to implement geographically targeted interventions that address community-level transmission to control RR/MDR-TB in Rwanda effectively.

Rwanda↗

PubMed1999

Rapid DNA mutation identification and fingerprinting using base excision sequence scanning.

Base excision sequence scanning (BESS) is a new polymerase chain reaction (PCR)-based mutation scanning method that locates and identifies all DNA mutations. The BESS method consists of two procedures that generate "T" (BESS T-Scan) and "G" ladders (BESS G-Tracker) analogous to T and G ladders of dideoxy sequencing. The BESS procedures are simple to perform and require no special equipment or gels, no reaction optimization beyond PCR, and no heteroduplex formation. The samples are analyzed on standard sequencing gels or on automated DNA sequencers, and the data produced are easy to interpret, requiring a simple comparison of the sequence of normal and mutant DNA. The BESS method is versatile, having applications not only for mutation detection, but also single nucleotide polymorphism (SNP) discovery and analysis, DNA fingerprinting (including viral and bacterial typing), and clone identification. In this study, we utilize BESS in two of these applications: detection of a point mutation in BRCA1, and DNA typing of human papilloma virus (HPV).

BRCA1 Protein↗

PubMed2005

Haplotype analysis of the COMT-ARVCF gene region in Israeli anorexia nervosa family trios.

Anorexia nervosa (AN) is a severe and complex psychiatric disorder with a significant genetic contribution. Previously, we found an association between AN and the 158Val/Met polymorphism of the catechol-O-methyltransferase (COMT) gene in a family-based study of 51 Israeli AN trios. In the present study, we extended the original sample to include 85 family trios [66 AN restricting (AN-R) and 19 bingeing/purging (AN-BP) subtype] and performed a family-based transmission disequilibrium test (TDT) analysis for five SNPs in the COMT and two in the adjacent ARVCF gene. Association was found between AN-R and several SNPs in the COMT-ARVCF region including the 158Val/Met polymorphism. TDT analysis of 5-SNP haplotypes in AN-R trios revealed an overall statistically significant transmission disequilibrium (P < 0.001). Specifically, haplotype B [COMT-186C-408G-472G(158Val)-ARVCF-659C(220Pro)-524T(175Val)] was preferentially transmitted (P < 0.001) from parents of AN-R patients to their affected daughters, while haplotype A [COMT-186T-408C-472A(158Met)-ARVCF-659T(220Leu)-524C(175Ala)] was preferentially (P = 0.01) not transmitted. Haplotype B was associated with increased risk (RR 3.38; 0.95CI 1.98-6.43) while haplotype A exhibited a protective effect (RR 0.40; 0.95CI 0.21-0.70) for AN-R. Preferential transmission of the risk alleles and haplotypes from the parents was mostly contributed by the fathers. No significant transmission disequilibrium of alleles or haplotypes was found for AN-BP trios. The risk and protective haplotypes may carry molecular variations in the COMT gene or its vicinity that are relevant to the pathophysiology of restrictive anorexia nervosa in the Israeli-Jewish population.

Adolescent↗

PubMed2006

High-density single nucleotide polymorphism screen in a large multiplex neural tube defect family refines linkage to loci at 7p21.1-pter and 2q33.1-q35.

BACKGROUND: Neural tube defects (NTDs) are considered complex, with both genetic and environmental factors implicated. To date, no major causative genes have been identified in humans despite several investigations. The first genomewide screen in NTDs demonstrated evidence of linkage to chromosomes 7 and 10. This screen included 44 multiplex families and consisted of 402 microsatellite markers spaced approximately 10 cM apart. Further investigation of the genomic screen data identified a single large multiplex family, pedigree 8776, as primarily driving the linkage results on chromosome 7. METHODS: To investigate this family more thoroughly, a high-density single nucleotide polymorphism (SNP) screen was performed. Two-point and multipoint linkage analyses were performed using both parametric and nonparametric methods. RESULTS: For both the microsatellite and SNP markers, linkage analysis suggested the involvement of a locus or loci proximal to the telomeric regions of chromosomes 2q and 7p, with both regions generating a LOD* score of 3.0 using a nonparametric identity by descent relative sharing method. CONCLUSIONS: The regions with the strongest evidence for linkage map proximal to the telomeres on these two chromosomes. In addition to mutations and/or variants in a major gene, these loci may harbor a microdeletion and/or translocation; potentially, polygenic factors may also be involved. This single family may be promising for narrowing the search for NTD susceptibility genes.

Chromosomes, Human, Pair 2↗

PubMed2002

Real-time PCR for monitoring minimal residual disease and chimerism in patients after allogeneic transplantation.

Real-time PCR is a new fluorometric method for cycle-to-cycle quantification of PCR product growth rates. The real-time PCR method is fast and associated with a high reproducibility rate. It is used more often for monitoring MRD and chimerism in patients after allogeneic stem cell transplantation (SCT). There are real-time PCR methods for patients with CML, AML and ALL patients with inv(16), t(8;21), t(15;17); t(1;19) and other chromosomal aberrations. For patients with AML monitoring MRD is useful to identify patients who were at high risk for relapse after receiving chemotherapy. In patients with CML monitoring MRD might be helpful to assess success of after allogeneic SCT, or response to therapies with interferon alfa or STI 571. We found, that it is possible to estimate the relapse stage in CML after SCT by the amount of bcr-abl fusion transcript detected using a real-time PCR method. The median measured bcr-abl amount differ significantly (P<0.001) between the various stages, which has relevant clinical implications because it enables early therapeutic decisions in relapsing patients after transplant as e.g. the application of DLI to induce graft-versus-leukemia effects. Using real-time PCR it is possible to detect differences at alleles between recipient and donor at a single nucleotide basis (SNP) for chimerism analysis. The real-time PCR method enables to achieve a high a sensitivity of up to 1x10(-4), which is much more sensitive than all other chimerism methods including VNTR-PCR, STR-PCR. Furthermore, chimerism in male recipients with a female donor can be monitored also by detecting y-chromosome specific sequences by real-time PCR after transplant, which might be the most sensitive method to detect host type gene sequences. All in all, new real-time PCR methods offer a fast, reliable and very sensitive method to evaluate MRD and chimerism in patients after allogeneic SCT and therefore, to help to identify patients who are at high risk for leukemic relapse.

Hematopoietic Stem Cell Transplantation↗

PubMed2005

Variants in Deleted in AZoospermia-Like (DAZL) are correlated with reproductive parameters in men and women.

Qualitative and quantitative defects in human germ cell production that result in infertility are common and determined at least in part by genetic factors [Matzuk and Lamb, Nat Cell Biol 4(Suppl):s41-s49, 2002]. Yet, very few genes that are associated with germ cell defects in humans have been identified. In this study, we examined whether variants of the Deleted in AZoospermia-Like (DAZL) gene are associated with measures of germ cell production in three distinct populations of men and women. We identified 95 sequence variants in DAZL and further analyzed twelve single nucleotide polymorphisms (SNPs) that were present across ethnicities. We found that seven of the twelve SNPs were associated with at least one of the parameters studied (age at premature ovarian failure or menopause, total sperm count, or total motile sperm count). Surprisingly, many alleles exhibited opposing effects in men and women, which may be a result of different genetic requirements in male and female germ cells. Single SNP and haplotype analysis suggested that SNPs in the DAZL gene may act jointly to affect common reproductive characteristics in the human population.

Adolescent↗

PubMed2006

Association of specific haplotypes of neurotrophic tyrosine kinase receptor 2 gene (NTRK2) with vulnerability to nicotine dependence in African-Americans and European-Americans.

BACKGROUND: The gene encoding neurotrophic tyrosine kinase receptor 2 (NTRK2) has been localized to a region on chromosome 9q22-q23 that showed a "suggestive" linkage to nicotine dependence (ND) in our previous linkage analyses. However, no association of NTRK2 with ND has been identified. METHODS: Family-based association analyses of 2037 participants (1366 African Americans [AA], 671 European Americans [EA]) representing 602 nuclear families were performed to evaluate association of nine single nucleotide polymorphisms (SNPs) within NTRK2 with ND. RESULTS: Individual SNP-based association analysis indicated that in the EA sample, SNPs rs1659400 and rs1187272 were significantly associated with at least one adjusted ND measure. Haplotype analysis revealed that even after Bonferroni correction, the haplotype T-T-A of rs1659400-rs1187272-rs1122530 had a highly significant positive association, with adjusted ND measures in the EA sample (max Z = 3.78; p = .0001, frequency 59.9%). We further identified a major haplotype, T-G-C-A-A (26%), formed by rs993315-rs736744-rs920776-rs4075274-rs729560, which showed a significant positive association (max Z = 2.97, p = .003) with adjusted ND measures in the AA sample. CONCLUSIONS: These results strongly suggest that NTRK2 is a susceptibility gene for ND. These findings imply that NTRK2 plays a role in the etiology of ND and represents an important biological candidate for further investigation.

Adult↗

PubMed2004

Odorant and vomeronasal receptor genes in two mouse genome assemblies.

Odorant receptors (ORs) and vomeronasal receptors (V1Rs and V2Rs) are large superfamilies of chemosensory receptors. As an extension of previous research using the 2001 Celera mouse genome assembly, we analyzed OR and V1R genes in the 2002 public mouse genome assembly. We identified 1403 OR genes (1068 potentially intact) and 332 V1R genes (164 potentially intact) in this C57BL/6J mouse genome. This expands the mouse OR and V1R superfamilies by adding approximately 100 OR and approximately 40 V1R potentially intact genes. The description of the genomic distribution of OR genes is more complete and accurate, and two major errors in OR gene distribution in the 2001 Celera assembly were corrected. For the first time, the complete genomic distribution of V1R genes was investigated in detail and placed in context with that of OR genes. V1R genes, like OR genes, tend to form clusters of similar genes in the genome. Comparison between the two genome assemblies revealed a high rate of single-nucleotide polymorphisms (SNPs) in both OR and V1R genes. The high ratio of nonsynonymous SNPs over synonymous SNPs in V1R genes suggests positive selection for these genes, possibly favoring species-specific and strain-specific pheromone detection. In addition, detailed analysis of the SNP rate aided in the identification of key residues in ORs.

Animals↗

PubMed2006

Genetic mapping of a 17q chromosomal region linked to obesity phenotypes in the IRAS family study.

OBJECTIVE: Obesity is widely accepted to be influenced by both environmental and genetic factors. Several recent studies have used the positional cloning approach in an attempt to discover genes contributing to obesity. In the IRAS Family Study a genomewide scan was performed on 1425 individuals of Hispanic descent (90 extended pedigree families) to identify regions of the genome linked to obesity phenotypes. METHODS: Nonparametric QTL linkage analysis was performed using a variance components approach. The genome scan was performed in two phases: an initial genome scan in 45 families and a replication scan in 45 families. Fine mapping and candidate gene analyses were also performed. General estimating equations (GEE1) and quantitative pedigree disequilibrium tests (QPDT) were used for association analysis of single SNP and haplotype data. RESULTS: Evidence for linkage to obesity traits was observed in each scan on the long arm of chromosome 17. When data from both scans was combined, a region on chromosome 17q was identified with evidence of linkage to visceral adipose tissue (VAT; LOD 3.11), waist circumference (WAIST) (LOD 2.5) and body mass index (BMI) (LOD 2.81). Nine additional microsatellite markers were identified and genotyped on all Hispanic individuals, with a mean marker density of approximately 1 marker/3 cM. Evidence of linkage remained significant with LOD 3.05 for VAT, LOD 2.44 for BMI and LOD 1.92 for WAIST. Fine mapping analyses suggest the possibility of two different obesity loci. In addition, the LOD - 1 interval of the major VAT peak decreased from 83-108 to 95-111 cM. Three positional candidate genes under the peak: somatostatin receptor 2 (SSTR2), galanin receptor 2 (GALR2), and growth hormone bound protein receptor 2 (GRB2) were chosen for detailed evaluation. Multiple polymorphisms within each candidate were genotyped and tested for association with the obesity phenotypes. Little evidence of association was detected between polymorphisms and obesity traits. CONCLUSION: In conclusion, replication of linkage and fine mapping suggest that a region on chromosome 17q contains a gene (or genes) that contributes to the genetic etiology of obesity with the strongest evidence for linkage to VAT. Candidate genes in the region do not appear to account for the evidence of linkage. Additional studies are necessary to identify the obesity-related polymorphisms.

Adult↗

PubMed2005

Haplotypes in the gene encoding protein kinase c-beta (PRKCB1) on chromosome 16 are associated with autism.

Autism is a developmental disorder characterized by impairments in social interaction and communication associated with repetitive patterns of interest or behavior. Autism is highly influenced by genetic factors. Genome-wide linkage and candidate gene association approaches have been used to try and identify autism genes. A few loci have repeatedly been reported linked to autism. Several groups reported evidence for linkage to a region on chromosome 16p. We have applied a direct physical identity-by-descent (IBD) mapping approach to perform a high-density (0.85 megabases) genome-wide linkage scan in 116 families from the AGRE collection. Our results confirm linkage to a region on chromosome 16p with autism. High-resolution single-nucleotide polymorphism (SNP) genotyping and analysis of this region show that haplotypes in the protein kinase c-beta gene are strongly associated with autism. An independent replication of the association in a second set of 167 trio families with autism confirmed our initial findings. Overall, our data provide evidence that the PRKCB1 gene on chromosome 16p may be involved in the etiology of autism.

Autistic Disorder↗

PubMed2026

Responding to a protracted tuberculosis outbreak: lessons from multiple rounds of investigation in a Chinese boarding school.

PURPOSE: This study analysed a multi-semester pulmonary tuberculosis (PTB) cluster outbreak in a Chinese boarding school to provide evidence for future epidemic control. METHODS: Contacts were screened via symptoms, infection tests and chest radiography. Screening expanded progressively from close contacts to same-floor contacts, then all students and staff. Whole-genome sequencing (WGS) with single nucleotide polymorphism (SNP) and bioinformatics analysis was used for lineage classification, transmission clustering (≤12 SNPs defining a cluster) and drug resistance prediction. RESULTS: From 2020 to 2022, 20 students were diagnosed with PTB, half laboratory-confirmed. Most cases clustered in class 16 and were epidemiologically linked to the primary case (case 0), who had household PTB exposure. Case 0 and case 1 had diagnostic delays exceeding 3 and 6 months, respectively. WGS of five isolates (case 1, 3, 4, 9 and 10) collected over three semesters showed all belonged to lineage 2 and differed by ≤12 SNPs, confirming the same transmission chain. The infection rate in class 16 (46.34%) was significantly higher than other case classes (19.05%) and classes without cases (8.27%) (χ2 = 61.169, p < 0.001). No new cases were detected during a one-year follow-up of students involved in the outbreak after the final round of screening, nor among household contacts of all cases followed up to the present. CONCLUSIONS: Lack of entry health examinations facilitated the outbreak. Delayed diagnosis, incomplete contact screening and absence of preventive treatment led to cross-semester persistence. The infection rate disparity confirms class 16 as the outbreak epicentre. Improving community case management, extending contact follow-up and enhancing cluster outbreak measures are recommended to prevent future outbreaks.

Humans↗

PubMed2006

A fine-scale linkage-disequilibrium measure based on length of haplotype sharing.

High-throughput genotyping technologies for SNPs have enabled the recent completion of the International HapMap Project (phase I), which has stimulated much interest in studying genomewide linkage-disequilibrium (LD) patterns. Conventional LD measures, such as D' and r(2), are two-point measurements, and their relationship with physical distance is highly noisy. We propose a new LD measure, Delta , defined in terms of the correlation coefficient for shared haplotype lengths around two loci, thereby borrowing information from multiple loci. A U-statistic-based estimator of Delta , which takes into consideration the dependence structure of the observed data, is developed and compared with an estimator based on the usual empirical correlation coefficient. Furthermore, we propose methods for inferring LD-decay rates and recombination hotspots on the basis of Delta . The results from coalescent-simulation studies and analysis of HapMap SNP data demonstrate that the proposed estimators of Delta are superior to the two most popular conventional LD measures, in terms of their close relationship with physical distance and recombination rate, their small variability, and their strong robustness to marker-allele frequencies. These merits may offer new opportunities for mapping complex disease genes and for investigating recombination mechanisms on the basis of better-quantified LD.

Alleles↗

PubMed2006

Dynamin-binding protein gene on chromosome 10q is associated with late-onset Alzheimer's disease.

The apolipoprotein E (APOE) gene has been consistently shown to be a major genetic risk factor; however, all cases of Alzheimer's disease (AD) cannot be attributed to the epsilon4 variant of APOE, because about half of AD patients have the APOE-epsilon3*3 genotype. To identify an additional genetic risk factor(s), we performed large-scale single nucleotide polymorphism (SNP)-based association analysis of 1526 late-onset AD patients and 1666 control subjects in a Japanese population. We prepared two independent sets consisting of exploratory and validation samples, respectively, with only the APOE-epsilon3*3 genotype, and first carried out genotyping for the exploratory set with 1206 SNPs in the region between 60 and 107 Mb on chromosome 10q that is implicated by linkage studies as containing an AD susceptibility locus. Thirty-five SNPs that showed significant values (P<0.01) were followed-up to detect any association with the validation samples. Finally, six SNPs exhibited replicated significant associations (P=0.000035-0.00048) on meta-analysis of both sets. These SNPs were clustered in a locus spanning 220 kb at genomic position 101 Mb, and three of the six SNPs were located in the dynamin-binding protein (DNMBP) gene. Quantitative real-time RT-PCR analysis demonstrated that neuropathologically confirmed AD brains exhibit a significant reduction of DNMBP mRNA compared with age-matched ones (P<0.0169). Thus, we confirmed the association of DNMBP with AD individuals with the APOE-epsilon3*3 genotype or lacking the epsilon4 allele, and DNMBP may be one of the susceptibility genes for AD.

Aged↗