Institution
Wellcome Trust Centre for Human Genetics
Facility•Oxford, United Kingdom•
About: Wellcome Trust Centre for Human Genetics is a facility organization based out in Oxford, United Kingdom. It is known for research contribution in the topics: Population & Genome-wide association study. The organization has 2122 authors who have published 4269 publications receiving 433899 citations.
Topics: Population, Genome-wide association study, Single-nucleotide polymorphism, Gene, Locus (genetics)
Papers published on a yearly basis
Papers
More filters
••
TL;DR: In this paper, a systematic whole-genome screen to identify regions exhibiting genetic linkage to rheumatoid arthritis (RA) was conducted to identify significant linkage (maximum logarithm of odds score 4.7 [P = 0.000003] at marker D6S276, 1 cM from HLA-DRB1).
Abstract: 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 × 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 × 10−5). Results of previous genome screens have suggested that 6 of these regions may be involved in RA susceptibility.
206 citations
••
TL;DR: A detailed BAC-/PAC-based sequence map of this interval is assembled, containing 152 sequence tagged sites (STSs), 20 known genes, and >7.75 Mb of completed genomic sequence in the KE family, and refinement of the SPCH1 interval to a region between new markers 013A and 330B is refined.
Abstract: The KE family is a large three-generation pedigree in which half the members are affected with a severe speech and language disorder that is transmitted as an autosomal dominant monogenic trait. In previously published work, we localized the gene responsible (SPCH1) to a 5.6-cM region of 7q31 between D7S2459 and D7S643. In the present study, we have employed bioinformatic analyses to assemble a detailed BAC-/PAC-based sequence map of this interval, containing 152 sequence tagged sites (STSs), 20 known genes, and >7.75 Mb of completed genomic sequence. We screened the affected chromosome 7 from the KE family with 120 of these STSs (average spacing 3.7 Mb distal to this, outside the current SPCH1 critical interval. Finally, we investigated the CAGH44 gene in affected individuals of the KE family, but we found no mutations in the currently known coding sequence. These studies represent further steps toward the isolation of the first gene to be implicated in the development of speech and language.
206 citations
••
TL;DR: It is proposed that an abnormal Nodal-Pitx2c pathway represents a unifying mechanism for the cardiovascular malformations observed in Cited2−/− mice, and that such mal Formations may be the sole manifestation of a laterality defect.
Abstract: Malformations of the septum, outflow tract and aortic arch are the most common congenital cardiovascular defects and occur in mice lacking Cited2, a transcriptional coactivator of TFAP2. Here we show that Cited2−/− mice also develop laterality defects, including right isomerism, abnormal cardiac looping and hyposplenia, which are suppressed on a mixed genetic background. Cited2−/− mice lack expression of the Nodal target genes Pitx2c, Nodal and Ebaf in the left lateral plate mesoderm, where they are required for establishing laterality and cardiovascular development. CITED2 and TFAP2 were detected at the Pitx2c promoter in embryonic hearts, and they activate Pitx2c transcription in transient transfection assays. We propose that an abnormal Nodal-Pitx2c pathway represents a unifying mechanism for the cardiovascular malformations observed in Cited2−/− mice, and that such malformations may be the sole manifestation of a laterality defect.
206 citations
••
Wellcome Trust Centre for Human Genetics1, Chang Gung University2, Max Planck Society3, University of Granada4, National Institute for Health Research5, University of Cambridge6, Sichuan University7, Harbin Medical University8, Zhengzhou University9, China Medical University (PRC)10, Chongqing Medical University11, Nanjing Medical University12, Zhejiang Chinese Medical University13, Capital Medical University14, Hebei Medical University15, Sun Yat-sen University16, Shanxi Medical University17, Jiangsu University18, University of Oxford19, Peking Union Medical College20, Virginia Commonwealth University21, East China Normal University22
TL;DR: It is demonstrated that changes in the amount of mtDNA and telomere length are consequences of stress and entering a depressed state and have important implications for understanding how stress causes the disease.
205 citations
••
TL;DR: A simulation algorithm is developed to generate high-density SNP data with short-range linkage disequilibrium based on empirical patterns of haplotype diversity that highlights substantial gains in power over single-locus tests for a wide range of disease models, despite overcorrection for multiple testing.
Abstract: We present a novel approach to disease-gene mapping via cladistic analysis of single-nucleotide polymorphism (SNP) haplotypes obtained from large-scale, population-based association studies, applicable to whole-genome screens, candidate-gene studies, or fine-scale mapping. Clades of haplotypes are tested for association with disease, exploiting the expected similarity of chromosomes with recent shared ancestry in the region flanking the disease gene. The method is developed in a logistic-regression framework and can easily incorporate covariates such as environmental risk factors or additional unlinked loci to allow for population structure. To evaluate the power of this approach to detect disease-marker association, we have developed a simulation algorithm to generate high-density SNP data with short-range linkage disequilibrium based on empirical patterns of haplotype diversity. The results of the simulation study highlight substantial gains in power over single-locus tests for a wide range of disease models, despite overcorrection for multiple testing.
204 citations
Authors
Showing all 2127 results
Name | H-index | Papers | Citations |
---|---|---|---|
Mark I. McCarthy | 200 | 1028 | 187898 |
John P. A. Ioannidis | 185 | 1311 | 193612 |
Gonçalo R. Abecasis | 179 | 595 | 230323 |
Simon I. Hay | 165 | 557 | 153307 |
Robert Plomin | 151 | 1104 | 88588 |
Ashok Kumar | 151 | 5654 | 164086 |
Julian Parkhill | 149 | 759 | 104736 |
James F. Wilson | 146 | 677 | 101883 |
Jeremy K. Nicholson | 141 | 773 | 80275 |
Hugh Watkins | 128 | 524 | 91317 |
Erik Ingelsson | 124 | 538 | 85407 |
Claudia Langenberg | 124 | 452 | 67326 |
Adrian V. S. Hill | 122 | 589 | 64613 |
John A. Todd | 121 | 515 | 67413 |
Elaine Holmes | 119 | 560 | 58975 |