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See detailIdentification of molecular components of the host-microbiota-connectome by using "Omics Approaches"
Mariman, Rob ULg; Coppieters, Wouter ULg; Elansary, Mahmoud ULg et al

Poster (2014, April 24)

The host immune system plays an critical role in maintaining homeostasis with resident microbial communities, therefore ensuring that the complex symbiotic relationship is maintained. At the same time ... [more ▼]

The host immune system plays an critical role in maintaining homeostasis with resident microbial communities, therefore ensuring that the complex symbiotic relationship is maintained. At the same time, resident microbiota contribute to host nutrition and energy balance and to the development or maintenance of a robust immune system. Dysbiosis of the microbiota is associated with various immunological disorders, including inflammatory bowel diseases (IBD). Both genetic and environmental factors are implicated in this disturbance; however, the relative contributions of these two factors, and the mechanism by which they interact remain unclear. Recently, we started a project that aims to identify molecular components of the hostmicrobiota-connectome by taking advantage of common variation in – on the one hand – the genome, transcriptome and metabolome of the host, and – on the other hand – the composition of its gut microbiota. We will take advantage of the already established CEDAR cohort that provides integrated genetic (SNP genotypes) and transcriptome data (circulating immune cells subset, as well as samples from various anatomical locations in the intestine). We will further enrich the dataset in this cohort with metabolome (plasma), and gut microbiota data (16srRNA sampled at the ileum, colon, and rectum). The CEDAR cohort is composed of healthy individuals and is therefore more suitable to study effect of common risk variants than (IBD) patients, since analysis of samples from patients suffering from active inflammation may only give insight in ongoing patho-physiological processes, that are likely to mask the primum movens events. Next, we will study the overlap between the identified components of the HMC network identified and the ~160 GWAS-identified risk loci for IBD. We anticipate to reveal novel connections between the microbiota and IBD by this integrative “omics” approach, thereby shedding new light on the pathogenesis of IBD. Latest results will be presented with respect to the microbiota composition of from different anatomical locations in the intestine using the V2 and V5-6 regions of the bacterial 16S rRNA. [less ▲]

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See detailIdentifying Inflammatory Bowel Disease causative genes through trans-eQTLs mapping within GWAS loci
Docampo Martínez, Elisa ULg; Theatre, Emilie ULg; Dmitrieva, Joelia Borisnova ULg et al

Poster (2014, April 24)

Lifetime prevalence of inflammatory bowel disease (IBD) is reaching an alarming rate of >1/400 in industrialized societies. Improved understanding of disease pathogenesis is essential to develop more ... [more ▼]

Lifetime prevalence of inflammatory bowel disease (IBD) is reaching an alarming rate of >1/400 in industrialized societies. Improved understanding of disease pathogenesis is essential to develop more effective preventive, diagnostic and therapeutic measures. Genome-wide association studies (GWAS) have identified ~ 160 risk loci contributing to inherited predisposition to IBD, leading to the identification of new perturbed pathways and potential drug targets. Nevertheless, causative genes and variants remain unknown for the vast majority of risk loci. GWAS loci are likely to be regulatory and therefore alter expression levels of other genes. We hypothesize that if an IBD associated SNP is an expression quantitative loci (eQTL)-the " disease-association pattern " (DAP) should mirror the " eQTL association pattern " (EAP) of the causative gene if looking in the right target tissue(s). With this premise, our project aims to detect causative genes implicated in IBD's susceptibility through the evaluation of trans-eQTLs within GWAS loci. To this purpose, nine blood cell types and ileal, colonic and rectal biopsies have been collected for 330 healthy individuals of Northern European descent. All individuals have been genotyped with the OmniExpress Illumina array interrogating > 700K genetic variants. Transcriptome analysis has been conducted for all individuals and all cell/tissue types using Illumina HT12 arrays interrogating > 47,000 transcripts. Genotype and transcriptome data have undergone rigorous quality control. Transcriptome data have been pretreated variance stabilizing transformation, QQ normalization and correction for random and fixed effects in each cell type. Only expression probes mapped against Refseq have been considered. Genomic positions have been recovered and probes mapping to more than one genomic position (taking into account splice junctions with Tophat software) with a 96% identity have been discarded. Trans-eQTL mapping will be conducted on a SNP-by-SNP basis using linear regression (additive model) with PLINK software. In order to circumvent genome wide multiple testing penalty, we will test for a given SNP in the genome, any evidence for an excess of low p-values when testing its effect on the expression of genes located on other chromosomes or far away on the same chromosome. Confirmation of putative multigene transregulators will afterwards be performed by RNAseq experiments. We will then quantify the resemblance between DAP in the 160 GWAS-identified risk loci (raw data from IIBDGC plus imputed data) and " multigene trans-EAP " with Spearman's rank correlation. We will also evaluate the biological relevance of this list by performing a network analysis after adding the identified trans targets to the list of previously identified positional candidate genes (mapping to GWAS-identified IBD risk loci). Finally, as a the ultimate proof of causality, the selected genes will be resequenced in 3,000 IBD cases and 3,000 controls, using 600 DNA pools of 10 individuals with Illumina Truseq Amplicon. With this strategy, we expect to detect new causative variants that may constitute new drug targets for IBD. Latest results will be presented. [less ▲]

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See detailCombined use of GWAS and eQTL information to identify genes controlling platelet biology
Gori, Ann-Stephan ULg; LECUT, Christelle ULg; Theatre, Emilie ULg et al

Poster (2014, April 24)

Genome Wide Association Studies (GWAS) have identified at least 68 loci involved in megakaryopoiesis and platelet formation. As for all GWAS, identified risk loci span hundreds of kilobases encompassing ... [more ▼]

Genome Wide Association Studies (GWAS) have identified at least 68 loci involved in megakaryopoiesis and platelet formation. As for all GWAS, identified risk loci span hundreds of kilobases encompassing multiple genes, such that causative variants and genes remain largely unknown. To aid in the identification of causative genes underlying GWAS hits for platelet function (as well as other phenotypes including common complex diseases), we have generated a dataset (" CEDAR ") comprising genome-wide SNP and transcriptome data on nine primary cell types, including platelets, for 330 healthy Caucasian individuals. In addition, we have measured platelet counts and volume, as well as platelet reactivity to ADP, collagen and thrombin-related peptide for all these individuals. After extensive quality control, the ensuing data set has been used to identify (i) QTL influencing platelet count, volume and reactivity, and (ii) cis-and transacting eQTL operating in platelets. To aid in the identification of genes underlying platelet biology, we are applying a recently developed method to search for correlations between association patterns with platelet phenotypes and eQTL association patterns. Such findings would strongly incriminate the corresponding genes (affected by the eQTL) as being causally involved in determining the cognate platelet phenotype. Latest results will be presented. [less ▲]

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See detailResequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease.
Momozawa, Yukihide ULg; Mni, Myriam ULg; Nakamura, Kayo ULg et al

in Nature Genetics (2011), 43(1), 43-7

Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most approximately 20 ... [more ▼]

Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most approximately 20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease. [less ▲]

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See detailEvidence for significant overlap between common risk variants for Crohn's disease and ankylosing spondylitis.
Laukens, Debby; Georges, Michel ULg; Libioulle, Cécile ULg et al

in PLoS ONE (2010), 5(11), 13795

BACKGROUND: A multicenter genome-wide association scan for Crohn's Disease (CD) has recently reported 40 CD susceptibility loci, including 29 novel ones (19 significant and 10 putative). To gain insight ... [more ▼]

BACKGROUND: A multicenter genome-wide association scan for Crohn's Disease (CD) has recently reported 40 CD susceptibility loci, including 29 novel ones (19 significant and 10 putative). To gain insight into the genetic overlap between CD and ankylosing spondylitis (AS), these markers were tested for association in AS patients. PRINCIPAL FINDINGS: Two previously established associations, namely with the MHC and IL23R loci, were confirmed. In addition, rs2872507, which maps to a locus associated with asthma and influences the expression of the ORMDL3 gene in lymphoblastoid cells, showed a significant association with AS (p = 0.03). In gut biopsies of AS and CD patients, ORMDL3 expression was not significantly different from controls and no correlation was found with the rs2872507 genotype (Spearman's rho: -0.067). The distribution of p-values for the remaining 36 SNPs was significantly skewed towards low p-values unless the top 5 ranked SNPs (ORMDL3, NKX2-3, PTPN2, ICOSLG and MST1) were excluded from the analysis. CONCLUSIONS: Association analysis using risk variants for CD led to the identification of a new risk variant associated with AS (ORMDL3), underscoring a role for ER stress in AS. In addition, two known and five potentially relevant associations were detected, contributing to common susceptibility of CD and AS. [less ▲]

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See detailCommon variants at five new loci associated with early-onset inflammatory bowel disease.
Imielinski, Marcin; Baldassano, Robert N; Griffiths, Anne et al

in Nature Genetics (2009), 41(12), 1335-40

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide ... [more ▼]

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD. [less ▲]

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See detailGenome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease
Barrett, Jeffrey C.; Hansoul, Sarah ULg; Nicolae, Dan L. et al

in Nature Genetics (2008), 40(8), 955-62

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 ... [more ▼]

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. [less ▲]

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See detailNovel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4.
Libioulle, Cécile ULg; Louis, Edouard ULg; Hansoul, Sarah ULg et al

in PLoS Genetics (2007), 3(4), 538-543

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 ... [more ▼]

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 x 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. [less ▲]

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See detailGenetic and functional confirmation of the causality of the DGAT1 K232A quantitative trait nucleotide in affecting milk yield and composition
Grisart, B.; Farnir, Frédéric ULg; Karim, Latifa ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2004), 101(8), 2398-2403

We recently used a positional cloning approach to identify a nonconservative lysine to alanine substitution (K232A) in the bovine DGAT1 gene that was proposed to be the causative quantitative trait ... [more ▼]

We recently used a positional cloning approach to identify a nonconservative lysine to alanine substitution (K232A) in the bovine DGAT1 gene that was proposed to be the causative quantitative trait nucleotide underlying a quantitative trait locus (QTL) affecting milk fat composition, previously mapped to the centromeric end of bovine chromosome 14. We herein generate genetic and functional data that confirm the causality of the DGAT1 K232A mutation. We have constructed a high-density single-nucleotide polymorphism map of the 3.8-centimorgan BULGE30-BULGE9 interval containing the QTL and show that the association with milk fat percentage maximizes at the DGAT1 gene. We provide evidence that the K allele has undergone a selective sweep. By using a baculovirus expression system, we have expressed both DGAT1 alleles in Sf9 cells and show that the K allele, causing an increase in milk fat percentage in the live animal, is characterized by a higher V-max in producing triglycerides than the A allele. [less ▲]

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See detailPositional candidate cloning of a QTL in dairy cattle: Identification of a missense mutation in the bovine DGAT1 gene with major effect on milk yield and composition
Grisart, B.; Coppieters, Wouter ULg; Farnir, Frédéric ULg et al

in Genome Research (2002), 12(2), 222-231

We recently mapped a quantitative trait locus (QTL) with a major effect on milk composition-particularly fat content-to the centromeric end of bovine chromosome 14. We subsequently exploited linkage ... [more ▼]

We recently mapped a quantitative trait locus (QTL) with a major effect on milk composition-particularly fat content-to the centromeric end of bovine chromosome 14. We subsequently exploited linkage disequilibrium to refine the map position of this QTL to a 3-cM chromosome interval bounded by microsatellite markers BULGE13 and BULGE09. We herein report the positional candidate cloning of this QTL, involving (I) the construction of a BAC contig spanning the corresponding marker interval, (2) the demonstration that a very strong candidate gene, acylCoA:diacylglycerol acyltransferase (DGATf), maps to that contig, and (3) the identification of a nonconservative K232A substitution in the DGAT1 gene with a major effect on milk fat content and other milk characteristics. [less ▲]

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See detailSimultaneous mining of linkage and linkage disequilibrium to fine map quantitative trait loci in outbred half-sib pedigrees: Revisiting the location of a quantitative trait locus with major effect on milk production on bovine chromosome 14
Farnir, Frédéric ULg; Grisart, B.; Coppieters, Wouter ULg et al

in Genetics (2002), 161(1), 275-287

A maximum-likelihood QTL mapping method that simultaneously exploits linkage and linkage disequilibrium and that is applicable in outbred half-sib pedigrees is described. The method is applied to fine map ... [more ▼]

A maximum-likelihood QTL mapping method that simultaneously exploits linkage and linkage disequilibrium and that is applicable in outbred half-sib pedigrees is described. The method is applied to fine map a QTL with major effect on milk fat content in a 3-cM marker interval on proximal BTA14. This proximal location is confirmed by applying a haplotype-based association method referred to as recombinant ancestral haplotype analysis. The origin of the discrepancy between the QTL position derived in this work and that of a previous analysis is examined and shown to be due to the existence of distinct marker haplotypes associated with QTL alleles having large substitution effects. [less ▲]

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See detailExtensive Genome-Wide Linkage Disequilibrium in Cattle
Farnir, Frédéric ULg; Coppieters, Wouter ULg; Arranz, J. J. et al

in Genome Research (2000), 10(2), 220-7

A genome-wide linkage disequilibrium (LD) map was generated using microsatellite genotypes (284 autosomal microsatellite loci) of 581 gametes sampled from the dutch black-and-white dairy cattle population ... [more ▼]

A genome-wide linkage disequilibrium (LD) map was generated using microsatellite genotypes (284 autosomal microsatellite loci) of 581 gametes sampled from the dutch black-and-white dairy cattle population. LD was measured between all marker pairs, both syntenic and nonsyntenic. Analysis of syntenic pairs revealed surprisingly high levels of LD that, although more pronounced for closely linked marker pairs, extended over several tens of centimorgan. In addition, significant gametic associations were also shown to be very common between nonsyntenic loci. Simulations using the known genealogies of the studied sample indicate that random drift alone is likely to account for most of the observed disequilibrium. No clear evidence was obtained for a direct effect of selection ("Bulmer effect"). The observation of long range disequilibrium between syntenic loci using low-density marker maps indicates that LD mapping has the potential to be very effective in livestock populations. The frequent occurrence of gametic associations between nonsyntenic loci, however, encourages the combined use of linkage and linkage disequilibrium methods to avoid false positive results when mapping genes in livestock. [less ▲]

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See detailFine-Mapping of Quantitative Trait Loci by Identity by Descent in Outbred Populations: Application to Milk Production in Dairy Cattle
Riquet, J.; Coppieters, Wouter ULg; Cambisano, Nadine ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (1999), 96(16), 9252-9257

We previously mapped a quantitative trait locus (QTL) affecting milk production to bovine chromosome 14. To refine the map position of this QTL, we have increased the density of the genetic map of ... [more ▼]

We previously mapped a quantitative trait locus (QTL) affecting milk production to bovine chromosome 14. To refine the map position of this QTL, we have increased the density of the genetic map of BTA14q11-16 by addition of nine microsatellites and three single nucleotide polymorphisms. Fine-mapping of the QTL was accomplished by a two-tiered approach. In the first phase, we identified seven sires heterozygous "Qq" for the QTL by marker-assisted segregation analysis in a Holstein-Friesian pedigree comprising 1,158 individuals. In a second phase, we genotyped the seven selected sires for the newly developed high-density marker map and searched for a shared haplotype flanking an hypothetical, identical-by-descent QTL allele with large substitution effect. The seven chromosomes increasing milk fat percentage were indeed shown to carry a common chromosome segment with an estimated size of 5 cM predicted to contain the studied QTL. The same haplotype was shown to be associated with increased fat percentage in the general population as well, providing additional support in favor of the location of the QTL within the corresponding interval. [less ▲]

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See detailMicrosatellite mapping of a major determinant of White Heifer Disease: the bovine roan locus
Charlier, Carole ULg; Denys, B.; Belanche, J. I. et al

in Mammalian Genome : Official Journal of the International Mammalian Genome Society (1996), 7

In the Belgian Blue Cattle breed, coat color variation is mainly under the influence of a single autosomal locus, the roan locus, characterized by a pair of codominant alleles: r + (black) and R (white ... [more ▼]

In the Belgian Blue Cattle breed, coat color variation is mainly under the influence of a single autosomal locus, the roan locus, characterized by a pair of codominant alleles: r + (black) and R (white). Heterozygous r + R animals have intermingled black and white hairs, yielding the ``blue'' phenotype typical of the breed. Major interest for the roan locus stems from its pleiotropic effect on fertility, owing to the critical role of the R allele in the determinism of White Heifer Disease. We describe the linkage mapping of the roan locus to bovine Chromosome (Chr) 5, in the interval between microsatellite markers BPI and AGLA293, with an associated lodscore of 11.2. Moreover, we map a candidate gene, the Steel locus coding for the mast cell growth factor, to bovine Chr 5. [less ▲]

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See detailThe mh gene causing double-muscling in cattle maps to bovine chromosome 2
Charlier, Carole ULg; Coppieters, Wouter ULg; Farnir, Frédéric ULg et al

in Mammalian Genome : Official Journal of the International Mammalian Genome Society (1995), 6

While the hereditary nature of the double-muscling phenotype (a generalized muscular hypertrophy documented in several cattle breeds) is well established, its precise segregation mode has remained ... [more ▼]

While the hereditary nature of the double-muscling phenotype (a generalized muscular hypertrophy documented in several cattle breeds) is well established, its precise segregation mode has remained controversial. Both monogenic models (autosomal dominant or recessive) and oligogenic models have been proposed. Using a panel of 213 bovine microsatellite markers, and an experimental pedigree obtained by backcrossing double-muscled (Belgian Blue)xconventional (Friesian) F1 dams to double-muscled sire, we have mapped a locus on bovine Chromosome (Chr) 2 that accounts for all the phenotypic variance in the backcross generation. This locus, referred to as mh (muscular hypertrophy), has been positioned with respect to a map composed of seven Chr 2-specific microsatellites, at 2 cM from the closest marker. This result confirms the validity in the Belgian Blue population of the monogenic model involving an autosomal mh locus, characterized by a wild-type + and a recessive mh allele, causing the double-muscling phenotype in the homozygous condition. The linkage relationship between the mh locus and the Chr 2 markers was confirmed in three informative pedigrees collected from the general Belgian Blue Cattle population, reinforcing the notion of genetic homogeneity of the double-muscling trait in this breed. This work paves the way towards marker-assisted selection for or against the double-muscling trait, and towards positional cloning of the corresponding gene. [less ▲]

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