Novel Crohn Disease Locus Identified by Genome-Wide Association Maps to a Gene Desert on 5p13.1 and Modulates Expression of PTGER4

To identify novel susceptibility loci for Crohn disease (CD), we undertook a genome-wide association study with more than 300,000 SNPs characterized in 547 patients and 928 controls. We found three chromosome regions that provided evidence of disease association with p-values between 10(−6) and 10(−9). Two of these (IL23R on Chromosome 1 and CARD15 on Chromosome 16) correspond to genes previously reported to be associated with CD. In addition, a 250-kb region of Chromosome 5p13.1 was found to contain multiple markers with strongly suggestive evidence of disease association (including four markers with p < 10(−7)). We replicated the results for 5p13.1 by studying 1,266 additional CD patients, 559 additional controls, and 428 trios. Significant evidence of association (p < 4 × 10(−4)) was found in case/control comparisons with the replication data, while associated alleles were over-transmitted to affected offspring (p < 0.05), thus confirming that the 5p13.1 locus contributes to CD susceptibility. The CD-associated 250-kb region was saturated with 111 SNP markers. Haplotype analysis supports a complex locus architecture with multiple variants contributing to disease susceptibility. The novel 5p13.1 CD locus is contained within a 1.25-Mb gene desert. We present evidence that disease-associated alleles correlate with quantitative expression levels of the prostaglandin receptor EP4, PTGER4, the gene that resides closest to the associated region. Our results identify a major new susceptibility locus for CD, and suggest that genetic variants associated with disease risk at this locus could modulate cis-acting regulatory elements of PTGER4

Existence of Natural and Projectively Equivariant

We study the existence of natural and projectively equivariant quantizations for differential operators acting between order 1 vector bundles over a smooth manifold M. To that aim, we make use of the Thomas-Whitehead approach of projective structures and construct a Casimir operator depending on a projective Cartan connection. We attach a scalar parameter to every space of differential operators, and prove the existence of a quantization except when this parameter belongs to a discrete set of resonant values.

Raw genotypes vs haplotype blocks for genome wide association studies by random forests

peer reviewedWe consider two different representations of the input data for genome-wide association studies using random forests, namely raw genotypes described by a few thousand to a few hundred thousand discrete variables each one describing a single nucleotide polymorphism, and haplotype block contents, represented by the combinations of about 10 to 100 adjacent and correlated genotypes. We adapt random forests to exploit haplotype blocks, and compare this with the use of raw genotypes, in terms of predictive power and localization of causal mutations, by using simulated datasets with one or two interacting effects

Raw genotypes vs haplotype blocks for genome wide association studies by random forests

peer reviewedWe consider two different representations of the input data for genome-wide association studies using random forests, namely raw genotypes described by a few thousand to a few hundred thousand discrete variables each one describing a single nucleotide polymorphism, and haplotype block contents, represented by the combinations of about 10 to 100 adjacent and correlated genotypes. We adapt random forests to exploit haplotype blocks, and compare this with the use of raw genotypes, in terms of predictive power and localization of causal mutations, by using simulated datasets with one or two interacting effects

Linkage Disequilibrium on the Bovine X Chromosome: Characterization and Use in Quantitative Trait Locus Mapping

We herein demonstrate that in the Holstein–Friesian dairy cattle population, microsatellites are as polymorphic on the X chromosome as on the autosomes but that the level of linkage disequilibrium between these markers is higher on the X chromosome than on the autosomes. The latter observation is not compatible with the small male-to-female ratio that prevails in this population and results in a higher gonosomal than autosomal effective population size. It suggests that the X chromosome undergoes distinct selective or mutational forces. We describe and characterize a novel Markovian approach to exploit this linkage disequilibrium to compute the probability that two chromosomes are identical-by-descent conditional on flanking marker data. We use the ensuing probabilities in a restricted maximum-likelihood approach to search for quantitative trait loci (QTL) affecting 48 traits of importance to the dairy industry and provide evidence for the presence of QTL affecting 5 of these traits on the bovine X chromosome

Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.

Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.Journal ArticleMeta-AnalysisResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe