Biomedical subjects

William Ollier

Publications and source records attributed to William Ollier.

13 recordsLinked to original sources

PubMed2005

Characterisation of the genomic architecture of human chromosome 17q and evaluation of different methods for haplotype block definition.

BACKGROUND: The selection of markers in association studies can be informed through the use of haplotype blocks. Recent reports have determined the genomic architecture of chromosomal segments through different haplotype block definitions based on linkage disequilibrium (LD) measures or haplotype diversity criteria. The relative applicability of distinct block definitions to association studies, however, remains unclear. We compared different block definitions in 6.1 Mb of chromosome 17q in 189 unrelated healthy individuals. Using 137 single nucleotide polymorphisms (SNPs), at a median spacing of 15.5 kb, we constructed haplotype block maps using published methods and additional methods we have developed. Haplotype tagging SNPs (htSNPs) were identified for each map. RESULTS: Blocks were found to be shorter and coverage of the region limited with methods based on LD measures, compared to the method based on haplotype diversity. Although the distribution of blocks was highly variable, the number of SNPs that needed to be typed in order to capture the maximum number of haplotypes was consistent. CONCLUSION: For the marker spacing used in this study, choice of block definition is not important when used as an initial screen of the region to identify htSNPs. However, choice of block definition has consequences for the downstream interpretation of association study results.

Chromosomes, Human, Pair 17↗

PubMed2005

UK Biobank: from concept to reality.

The UK Biobank is a major UK collaborative research project to recruit and follow longitudinally the health of 500,000 volunteers aged between 40-69 years. It will provide important biological samples and environmental exposure data. As such, it will constitute a resource for many future investigations of the separate and combined effects of genetic, environmental and lifestyle factors on human morbidity, mortality and health.

Adult↗

PubMed2004

Whole-genome scan, in a complex disease, using 11,245 single-nucleotide polymorphisms: comparison with microsatellites.

Despite the theoretical evidence of the utility of single-nucleotide polymorphisms (SNPs) for linkage analysis, no whole-genome scans of a complex disease have yet been published to directly compare SNPs with microsatellites. Here, we describe a whole-genome screen of 157 families with multiple cases of rheumatoid arthritis (RA), performed using 11,245 genomewide SNPs. The results were compared with those from a 10-cM microsatellite scan in the same cohort. The SNP analysis detected HLA*DRB1, the major RA susceptibility locus (P=.00004), with a linkage interval of 31 cM, compared with a 50-cM linkage interval detected by the microsatellite scan. In addition, four loci were detected at a nominal significance level (P<.05) in the SNP linkage analysis; these were not observed in the microsatellite scan. We demonstrate that variation in information content was the main factor contributing to observed differences in the two scans, with the SNPs providing significantly higher information content than the microsatellites. Reducing the number of SNPs in the marker set to 3,300 (1-cM spacing) caused several loci to drop below nominal significance levels, suggesting that decreases in information content can have significant effects on linkage results. In contrast, differences in maps employed in the analysis, the low detectable rate of genotyping error, and the presence of moderate linkage disequilibrium between markers did not significantly affect the results. We have demonstrated the utility of a dense SNP map for performing linkage analysis in a late-age-at-onset disease, where DNA from parents is not always available. The high SNP density allows loci to be defined more precisely and provides a partial scaffold for association studies, substantially reducing the resource requirement for gene-mapping studies.

Arthritis, Rheumatoid↗

PubMed2004

Investigation of susceptibility loci identified in the UK rheumatoid arthritis whole-genome scan in a further series of 217 UK affected sibling pairs.

OBJECTIVE: A previous whole-genome scan (WGS) of 182 UK rheumatoid arthritis (RA) affected sibling pair (ASP) families suggested linkage to HLA and 11 other chromosome regions. Replication of such findings in an independent cohort can help to distinguish true linkages from false-positive linkages. Since RA is a heterogeneous disease, some loci may be linked only in subsets of patients. Thus, the aim of this study was to investigate in an additional set of RA ASP families linkage to regions showing deviation in expected allele-sharing ratios in the UK WGS and to perform subset analysis on the combined cohort. METHODS: Twenty loci were investigated for linkage in 217 Caucasian UK RA ASPs. Stratification analysis was performed on the combined cohort of 377 RA ASP families to account for sex, RA severity, and the shared epitope (SE). RESULTS: None of the regions of linkage identified in the initial WGS achieved statistical significance in the second cohort. In contrast, after stratification analysis, 14 regions showed nominal evidence of linkage (logarithm of odds score >0.8) in one or more subgroups. In particular, the strength of evidence for linkage to chromosome 16p was increased in subsets of ASPs with younger age at disease onset (LOD score 2.38) and for linkage to chromosome 6q in female-female ASPs (LOD score 2.31) and in ASPs in which both siblings had 2 copies of the SE (LOD score 3.03). CONCLUSION: These results support the evidence for heterogeneity of RA. This information will inform the future design of association-based investigations as the search for disease genes in the linked regions begins.

Age of Onset↗

PubMed2003

No evidence of association between HLA-DRB1 and attention deficit hyperactivity disorder.

OBJECTIVES: There has been a recent resurgence in interest in the role of autoimmunity in childhood neuropsychiatric disorders. Significant association between HLA-DRB1 and attention deficit hyperactivity disorder (ADHD) in a case-control study of 31 subjects has been reported but there have been no other published studies following up these results. We attempted to replicate these findings. METHODS: In a well-characterized sample of 173 children with ADHD, using a fully automated sequence-specific oligonucleotide method for HLA genotyping, association between ADHD and HLA-DRB1 was tested for using the Transmission Disequilibrium Test and case-control analysis. RESULTS: Transmission Disequilibrium Test analysis yielded a chi-square of 10.694 with a simulated global P value of 0.1641 for the full sample, and a chi-square value of 11.307 with a simulated global P value of 0.1323 for the complete trios only. CONCLUSION: There was no evidence of association of HLA-DRB1 and ADHD.

Attention Deficit Disorder with Hyperactivity↗

PubMed2003

No evidence of association of two 5HT transporter gene polymorphisms and attention deficit hyperactivity disorder.

OBJECTIVES: Three studies to date have found evidence (or a trend for evidence) of linkage and association between the long allele of the 44 base pair repeat insertion/deletion 5-HTT functional polymorphism (5-HTTLPR) and attention deficit hyperactivity disorder (ADHD). In an attempt to replicate these findings, we examined this polymorphism and a variable number tandem repeat in the second intron of 5-HTT for association with ADHD. METHODS: One hundred and fifty children who met diagnostic criteria for ADHD and their parents (where available) were genotyped for these polymorphisms. Analysis was undertaken using the transmission disequilibrium test and haplotype analysis, as well as case-control comparisons using a control group of 121 individuals. RESULTS: No association between either the 5-HTTLPR or the variable number tandem repeat (VNTR) in ADHD was found (extended transmission disequilibrium test; P=0.37 and P=0.62, respectively). Haplotype analysis was also non-significant. Further analysis revealed no evidence of association in the subgroups of those without conduct disorder and in medication non-responders. CONCLUSIONS: Failure to replicate findings from previous studies may be due to a lack of statistical power. However, given recent findings by Kent et al. (2002) of association with another polymorphism in the 5HTT gene, we hypothesise that previous positive findings may have arisen by the LPR and VNTR being in linkage disequilibrium with the true susceptibility polymorphism.

Adult↗

PubMed2002

Association of DRD4 in children with ADHD and comorbid conduct problems.

Recent family and twin study findings suggest that ADHD when comorbid with conduct problems may represent a particularly familial and heritable form of ADHD. Although several independent groups have shown association between the DRD4 7 repeat allele and ADHD, others have failed to replicate this finding. Previous TDT analyses of UK and Eire samples had also been negative. We set out to further examine the role of DRD4 but selecting a subgroup of children with ADHD and comorbid conduct problems. Families were recruited from Manchester, Ireland, Birmingham and London clinics. From these, 67 children who fulfilled diagnostic criteria for ADHD and who displayed conduct disorder symptoms were selected. TDT analysis, which had previously yielded negative results for the total sample, showed evidence of association between DRD4 and "ADHD with conduct problems" (7 repeat allele-24 transmissions, 13 non-transmissions; one-tailed P=0.05). These results provide further support for the role of DRD4 in ADHD. Furthermore, these results when considered together with family and twin study findings, suggest that those children with ADHD and comorbid conduct problems may be particularly informative for molecular genetic studies of ADHD. Further work is needed to examine these phenotype issues.

Adolescent↗

PubMed2002

Association of familial and sporadic rheumatoid arthritis with a single corticotropin-releasing hormone genomic region (8q12.3) haplotype.

OBJECTIVE: Rheumatoid arthritis (RA) is a common disabling autoimmune disease with a complex genetic component. We have previously described linkage of a region of chromosome 8q12.3 with RA and association of the microsatellite marker CRHRA1 with RA in 295 affected sibling-pair families. In the current study we aimed to physically link the RA-associated marker with the corticotropin-releasing hormone (CRH) candidate gene, and to examine the genomic region for additional short tandem repeat (STR) genetic markers in order to clarify the association with RA. METHODS: We examined the association of 2 STR markers with disease in the original 295 multicase families and in a cohort of 131 simplex families to refine our understanding of this genetic region in disease susceptibility in sporadic and familial RA. Genomic library screening and sequencing were used to generate physical sequences in the CRH genomic region. Bioinformatic analysis of the sequence flanking the CRH structural gene was used to screen for additional STRs and other genetic features. Genotyping was carried out using a standard fluorescence approach. Estimations of haplotype frequencies were performed to assess linkage disequilibrium. The transmission disequilibrium test was performed using TRANSMIT. RESULTS: Physical cloning and sequencing analyses identified the genomic region linking the CRHRA1 marker and the CRH structural locus. Moreover, we identified a further STR, CRHRA2, which was in strong linkage disequilibrium with CRHRA1 (P = 4.0 x 10(-14)). A haplotype, CRHRA1*10;CRHRA2*14, was preferentially carried by unaffected parents at a frequency of 8.6% compared with the expected frequency of 3.1%. This haplotype was overtransmitted in the multiply affected families (P = 0.0077) and, similarly, in the simplex families (P = 0.024). Combined analysis of both family cohorts confirmed significant evidence for linkage (P = 4.9 x 10(-4)) and association (P = 5.5 x 10(-3)) for this haplotype with RA. CONCLUSION: In demonstrating significant linkage disequilibrium between these 2 markers, we have refined the disease-associated region to a single haplotype and confirmed the significance of this region in our understanding of the genetics of RA.

Arthritis, Rheumatoid↗

PubMed2002

Whole-genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom.

OBJECTIVE: To undertake a systematic whole-genome screen to identify regions exhibiting genetic linkage to rheumatoid arthritis (RA). METHODS: Two hundred fifty-two RA-affected sibling pairs from 182 UK families were genotyped using 365 highly informative microsatellite markers. Microsatellite genotyping was performed using fluorescent polymerase chain reaction primers and semiautomated DNA sequencing technology. Linkage analysis was undertaken using MAPMAKER/SIBS for single-point and multipoint analysis. RESULTS: Significant linkage (maximum logarithm of odds score 4.7 [P = 0.000003] at marker D6S276, 1 cM from HLA-DRB1) was identified around the major histocompatibility complex (MHC) region on chromosome 6. Suggestive linkage (P < 7.4 x 10(-4)) was identified on chromosome 6q by single- and multipoint analysis. Ten other sites of nominal linkage (P < 0.05) were identified on chromosomes 3p, 4q, 7p, 2 regions of 10q, 2 regions of 14q, 16p, 21q, and Xq by single-point analysis and on 3 sites (1q, 14q, and 14q) by multipoint analysis. CONCLUSION: Linkage to the MHC region was confirmed. Eleven non-HLA regions demonstrated evidence of suggestive or nominal linkage, but none reached the genome-wide threshold for significant linkage (P = 2.2 x 10(-5)). Results of previous genome screens have suggested that 6 of these regions may be involved in RA susceptibility.

Arthritis, Rheumatoid↗

PubMed2002

Linkage and association studies of single-nucleotide polymorphism-tagged tumor necrosis factor haplotypes in juvenile oligoarthritis.

OBJECTIVE: The presence of increased levels of tumor necrosis factor (TNF) in serum and synovial fluid of patients and the encouraging outcome of anti-TNF therapy have implicated TNFalpha in the etiopathogenesis of juvenile oligoarthritis. Although the locus is polymorphic, no study has investigated all TNF single-nucleotide polymorphisms (SNPs) with respect to disease. The aim of this study was to examine the association of multiple TNF SNPs with juvenile oligoarthritis and to construct and analyze SNP-tagged TNF haplotypes. METHODS: A total of 144 simplex families consisting of parent and affected child, as well as 88 healthy, unrelated control subjects were available for study. In these individuals, 9 polymorphic positions of TNF were typed by a high-throughput genotyping method based on the SNaPshot assay. The chi-square and extended transmission disequilibrium tests were used to test for association and linkage, respectively. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were also calculated. Haplotype-tagging SNPs (htSNPs) for the locus were identified by ordering the haplotypes according to their frequencies. RESULTS: The study detected association of several TNF SNPs and established linkage of the locus to juvenile oligoarthritis. The most significant association observed was between the intronic +851 TNF SNP and the persistent oligoarthritis subgroup (OR 3.86, 95% CI 1.6-9.2). Haplotype data mining showed that only 4 of the 9 SNPs need to be typed in order to capture the most frequent TNF haplotypes. CONCLUSION: The TNF locus is linked and associated with juvenile oligoarthritis. Information on the htSNPs can be useful in genetic studies of diseases in which TNF may be of relevance.

Adult↗

PubMed2002

Genetic approaches to the investigation of rheumatoid arthritis.

The investigation of genetic factors affecting the development or severity of rheumatoid arthritis may give new insights into the pathways involved in disease pathogenesis and lead to the identification of novel therapeutic targets. Recently, several novel approaches have been used in the attempt to unravel the complex association of rheumatoid arthritis with the human leukocyte antigen ( HLA ) gene region. It is clear that non-HLA genes are also involved in disease pathogenesis, and identifying them remains a challenge. In the past year, considerable headway has been made in this field, and some interesting strategies have been used. This review summarizes the results of many of the HLA and non-HLA studies and tries to draw lessons from the investigation of genetic susceptibility factors in other complex diseases.

Arthritis, Rheumatoid↗

PubMed2002

Lack of association between juvenile idiopathic arthritis and fas gene polymorphism.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a complex genetic disease of autoimmune etiology. Fas is a molecule with a pivotal role in apoptosis and hence in immune regulation. Elevated transcriptional levels of Fas in the synovial fluid of patients with JIA suggest that it might be implicated in disease etiopathogenesis. We investigated whether a polymorphism in the Fas promoter region (-670) confers susceptibility to JIA. METHODS: In this association study, 342 UK patients with JIA and 255 healthy individuals were genotyped for the polymorphism using polymerase chain reaction restriction fragment length polymorphism. Comparisons of the genotypic frequencies were made using chi-square analysis. RESULTS: No statistically significant differences were found when the genotype frequencies of the -670 Fas polymorphism were compared between the JIA cases and the control panel. Similarly, no differences were seen between the JIA subgroups, or when the patients were divided on the basis of rheumatoid factor or antinuclear antibody positivity. CONCLUSION: The -670 polymorphism of Fas does not appear to be associated with susceptibility to JIA.

Apoptosis↗

PubMed2002

Transforming growth factor-12 polymorphism and systemic lupus erythematosus.

OBJECTIVE: To determine whether transforming growth factor-beta2 (TGF-beta2) gene polymorphism is associated with systemic lupus erythematosus (SLE) susceptibility. TGF-beta is a multifunctional family of cytokines important in tissue repair, inflammation and immunoregulation. SLE is thought to be a T cell dependent autoimmune disorder with T cell dysfunction. Due to its known suppressive effects on interleukin 2 dependent T cell growth, TGF-beta2 is considered to be a candidate SLE susceptibility gene. Furthermore, SLE has been linked with a region to which the TGF-beta2 gene has been mapped. METHODS: Association studies were performed in 3 case-control populations, from Spain. Turkey, and UK, using a TGF-beta2 5'-untranslated region (5'-UTR) 4 base pair (bp) insertion polymorphism. Genotyping was performed using fluorescent labeled polymerase chain reaction product sizing. Results. No significant differences were detected in TGF-beta2 5'-UTR polymorphism allele frequencies between SLE patients and matched controls in the 3 populations studied. CONCLUSION: The 4 bp insertion polymorphism within the TGF-beta2 gene does not appear to be associated with SLE. However, this does not rule out the possible involvement of TGF-beta2 in the disease pathogenesis.

Alleles↗