Wellcome Trust Centre for Human Genetics

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.

Unusual haplotypic structure of IL8, a susceptibility locus for a common respiratory virus.

Abstract: Interleukin-8 (IL8) is believed to play a role in the pathogenesis of bronchiolitis, a common viral disease of infancy, and a recent U.K. family study identified an association between this disease and the IL8-251A allele. In the present study we report data, from a different set of families, which replicate this finding; combined analysis of 194 nuclear families through use of the transmission/disequilibrium test gives P = .001. To explore the underlying genetic cause, we identified nine single-nucleotide polymorphisms (SNPs) in a 7.6-kb segment spanning the IL8 gene and its promoter region and used six of these SNPs to define the haplotypic structure of the IL8 locus. The IL8-251A allele resides on two haplotypes, only one of which is associated with disease, suggesting that this may not be the functional allele. Europeans show an unusual haplotype genealogy that is dominated by two common haplotypes differing at multiple sites, whereas Africans have much greater haplotypic diversity. These marked haplotype-frequency differences give an F(ST) of.25, and, in the European sample, both Tajima's D statistic (D = 2.58, P = .007) and the Hudson/Kreitman/Aguade test (chi(2) = 4.9, P = .03) reject neutral equilibrium, suggesting that selective pressure may have acted on this locus.

Genome-wide significance for dense SNP and resequencing data.

Abstract: The problem of multiple testing is an important aspect of genome-wide association studies, and will become more important as marker densities increase. The problem has been tackled with permutation and false discovery rate procedures and with Bayes factors, but each approach faces difficulties that we briefly review. In the current context of multiple studies on different genotyping platforms, we argue for the use of truly genome-wide significance thresholds, based on all polymorphisms whether or not typed in the study. We approximate genome-wide significance thresholds in contemporary West African, East Asian and European populations by simulating sequence data, based on all polymorphisms as well as for a range of single nucleotide polymorphism (SNP) selection criteria. Overall we find that significance thresholds vary by a factor of >20 over the SNP selection criteria and statistical tests that we consider and can be highly dependent on sample size. We compare our results for sequence data to those derived by the HapMap Consortium and find notable differences which may be due to the small sample sizes used in the HapMap estimate.

Genetic susceptibility to coronary artery disease: from promise to progress

Abstract: Family history is an important independent risk factor for coronary artery disease (CAD), and identification of susceptibility genes for this common, complex disease is a vital goal. Although there has been considerable success in identifying genetic variants that influence well-known risk factors, such as cholesterol levels, progress in unearthing novel CAD genes has been slow. However, advances are now being made through the application of large-scale, systematic, genome-wide approaches. Recent findings particularly highlight the link between CAD and inflammation and immunity, and highlight the biological insights to be gained from a genetic understanding of the world's biggest killer.

The length of lipids bound to human CD1d molecules modulates the affinity of NKT cell TCR and the threshold of NKT cell activation

Abstract: CD1d-restricted lymphocytes recognize a broad lipid range. However, how CD1d-restricted lymphocytes translate T cell receptor (TCR) recognition of lipids with similar group heads into distinct biological responses remains unclear. Using a soluble invariant NKT (iNKT) TCR and a newly engineered antibody specific for α-galactosylceramide (α-GalCer)–human CD1d (hCD1d) complexes, we measured the affinity of binding of iNKT TCR to hCD1d molecules loaded with a panel of α-GalCer analogues and assessed the rate of dissociation of α-GalCer and α-GalCer analogues from hCD1d molecules. We extended this analysis by studying iNKT cell synapse formation and iNKT cell activation by the same panel of α-GalCer analogues. Our results indicate the unique role of the lipid chain occupying the hCD1d F′ channel in modulating TCR binding affinity to hCD1d–lipid complexes, the formation of stable immunological synapse, and cell activation. These data are consistent with previously described conformational changes between empty and loaded hCD1d molecules (Koch, M., V.S. Stronge, D. Shepherd, S.D. Gadola, B. Mathew, G. Ritter, A.R. Fersht, G.S. Besra, R.R. Schmidt, E.Y. Jones, and V. Cerundolo. 2005. Nat. Immunol 6:819–826), suggesting that incomplete occupation of the hCD1d F′ channel results in conformational differences at the TCR recognition surface. This indirect effect provides a general mechanism by which lipid-specific lymphocytes are capable of recognizing both the group head and the length of lipid antigens, ensuring greater specificity of antigen recognition.

Negligible impact of rare autoimmune-locus coding-region variants on missing heritability

Abstract: A search for variants in coding exons of 25 genome-wide association study risk genes in a large cohort of autoimmune patients finds that rare coding-region variants at known loci have a negligible role in common autoimmune disease susceptibility, arguing against the previously proposed rare-variant synthetic genome-wide association hypothesis. Although many common variants of modest-effect size have been identified in genome-wide association studies (GWAS), much of the heritability of complex traits remains unexplained. These authors looked for variants in coding exons of 25 GWAS risk genes in a large cohort of subjects with six autoimmune disease phenotypes and controls, and show that rare coding-region variants at known loci have at most a minor role in common autoimmune disease susceptibility. These results do not support the theory that the missing heritability for common autoimmune diseases is attributable to rare coding mutations at known loci, but are consistent with disease caused by many common-variant loci of weak effect. Genome-wide association studies (GWAS) have identified common variants of modest-effect size at hundreds of loci for common autoimmune diseases; however, a substantial fraction of heritability remains unexplained, to which rare variants may contribute1,2. To discover rare variants and test them for association with a phenotype, most studies re-sequence a small initial sample size and then genotype the discovered variants in a larger sample set3,4,5. This approach fails to analyse a large fraction of the rare variants present in the entire sample set. Here we perform simultaneous amplicon-sequencing-based variant discovery and genotyping for coding exons of 25 GWAS risk genes in 41,911 UK residents of white European origin, comprising 24,892 subjects with six autoimmune disease phenotypes and 17,019 controls, and show that rare coding-region variants at known loci have a negligible role in common autoimmune disease susceptibility. These results do not support the rare-variant synthetic genome-wide-association hypothesis6 (in which unobserved rare causal variants lead to association detected at common tag variants). Many known autoimmune disease risk loci contain multiple, independently associated, common and low-frequency variants, and so genes at these loci are a priori stronger candidates for harbouring rare coding-region variants than other genes. Our data indicate that the missing heritability for common autoimmune diseases may not be attributable to the rare coding-region variant portion of the allelic spectrum, but perhaps, as others have proposed, may be a result of many common-variant loci of weak effect7,8,9,10.