References of "Georges, Michel"
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See detailEctopic Expression of Retrotransposon-Derived PEG11/RTL1 Contributes to the Callipyge Muscular Hypertrophy.
Xu, Xuewen; Ectors, Fabien ULg; Davis, Erica E. et al

in PloS one (2015), 10(10), 0140594

The callipyge phenotype is an ovine muscular hypertrophy characterized by polar overdominance: only heterozygous +Mat/CLPGPat animals receiving the CLPG mutation from their father express the phenotype ... [more ▼]

The callipyge phenotype is an ovine muscular hypertrophy characterized by polar overdominance: only heterozygous +Mat/CLPGPat animals receiving the CLPG mutation from their father express the phenotype. +Mat/CLPGPat animals are characterized by postnatal, ectopic expression of Delta-like 1 homologue (DLK1) and Paternally expressed gene 11/Retrotransposon-like 1 (PEG11/RTL1) proteins in skeletal muscle. We showed previously in transgenic mice that ectopic expression of DLK1 alone induces a muscular hypertrophy, hence demonstrating a role for DLK1 in determining the callipyge hypertrophy. We herein describe newly generated transgenic mice that ectopically express PEG11 in skeletal muscle, and show that they also exhibit a muscular hypertrophy phenotype. Our data suggest that both DLK1 and PEG11 act together in causing the muscular hypertrophy of callipyge sheep. [less ▲]

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See detailA stop-gain in the laminin, alpha 3 gene causes recessive junctional epidermolysis bullosa in Belgian Blue cattle
Sartelet, Arnaud ULg; Harland, Chad ULg; Tamma, Nico ULg et al

in Animal Genetics (2015), 46(5), 566-570

Four newborn purebred Belgian Blue calves presenting a severe form of epidermolysis bullosa were recently referred to our heredo-surveillance platform. SNP array genotyping followed by autozygosity ... [more ▼]

Four newborn purebred Belgian Blue calves presenting a severe form of epidermolysis bullosa were recently referred to our heredo-surveillance platform. SNP array genotyping followed by autozygosity mapping located the causative gene in a 8.3-Mb interval on bovine chromosome 24. Combining information from (i) whole-genome sequencing of an affected calf, (ii) transcriptomic data from a panel of tissues and (iii) a list of functionally ranked positional candidates pinpointed a private G to A nucleotide substitution in the LAMA3 gene that creates a premature stop codon (p.Arg2609*) in exon 60, truncating 22% of the corresponding protein. The LAMA3 gene encodes the alpha 3 subunit of the heterotrimeric laminin-332, a key constituent of the lamina lucida that is part of the skin basement membrane connecting epidermis and dermis layers. Homozygous loss-of-function mutations in this gene are known to cause severe junctional epidermolysis bullosa in human, mice, horse, sheep and dog. Overall, our data strongly support the causality of the identified gene and mutation. [less ▲]

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See detailImproving the methodology for the detection of proviral integration sites in the host genome via high throughput sequencing.
Durkin, Keith ULg; Artesi, Maria ULg; Rosewick, Nicolas et al

in Retrovirology (2015, August 28), 12(1),

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See detailOn the use of the transmission disequilibrium test to detect pseudo-autosomal variants affecting traits with sex-limited expression
Elansary, Mahmoud ULg; Stinckens, Anneleen; Ahariz, Naïma ULg et al

in Animal Genetics (2015)

We herein describe the realization of a genome-wide association study for scrotal hernia and cryptorchidism in Norwegian and Belgian commercial pig populations. We have used the transmission ... [more ▼]

We herein describe the realization of a genome-wide association study for scrotal hernia and cryptorchidism in Norwegian and Belgian commercial pig populations. We have used the transmission disequilibrium test to avoid spurious associations due to population stratification. By doing so, we obtained genome-wide significant signals for both diseases with SNPs located in the pseudo-autosomal region in the vicinity of the pseudo-autosomal boundary. By further analyzing these signals, we demonstrate that the observed transmission disequilibria are artifactual. We determine that transmission bias at pseudo-autosomal markers will occur (i) when analyzing traits with sex-limited expression and (ii) when the allelic frequencies at the marker locus differ between X and Y chromosomes. We show that the bias is due to the fact that (i) sires will preferentially transmit the allele enriched on the Y (respectively X) chromosome to affected sons (respectively daughters) and (ii) dams will appear to preferentially transmit the allele enriched on the Y (respectively X) to affected sons (respectively daughters), as offspring inheriting the other allele are more likely to be non-informative. We define the conditions to mitigate these issues, namely by (i) extracting information from maternal meiosis only and (ii) ignoring trios for which sire and dam have the same heterozygous genotype. We show that by applying these rules to scrotal hernia and cryptorchidism, the pseudo-autosomal signals disappear, confirming their spurious nature. [less ▲]

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See detailPrioritizing likely causative genes in GWAS identified risk loci for immune-mediated inflammatory disorders using cell-type specific eQTL information.
Docampo Martínez, Elisa ULg; Fang, Ming ULg; Dmitrieva, Joelia Borisnova ULg et al

Poster (2015, May 05)

Background/Purpose: Immune-mediated inflammatory disorders (IMIDs) share many genetic risk factors. Pleiotropy may exist at different levels and most of the underlying mechanisms are still to be uncovered ... [more ▼]

Background/Purpose: Immune-mediated inflammatory disorders (IMIDs) share many genetic risk factors. Pleiotropy may exist at different levels and most of the underlying mechanisms are still to be uncovered. GWAS have identified hundreds of risk loci for IMIDs but causative genes have been identified in only a handful of cases. Recent fine-mapping efforts indicate that only a minority of risk variants are coding. This suggests that most risk variants will be regulatory hence affecting disease risk via eQTL effects. Methods: To aid in the identification of causative genes for IMIDs, we generated transcriptome information (HT12 arrays) for six blood cell types (CD4, CD8, CD19, CD14, CD15 and platelets) and intestinal biopsies at three anatomical locations (ileum, colon, rectum) for 350 healthy Caucasians. The same individuals were genotyped with SNP arrays interrogating > 700K variants, augmented by imputation from the 1KG project. To detect cis-eQTL we tested variants within 0.5 megabase windows centered on the tested probe. The nominal p-value of the best SNP within a cis-window was Sidak-corrected for the window-specific number of independent tests. The corresponding best, Sidak-corrected p-values for each probe were jointly used to estimate their respective false discovery rate.To identify likely causative genes in GWAS identified risk loci variants and also better understand pleiotropic effects, we (i) developed a method that quantifies the correlation between “disease association pattern” (DAP) and “eQTL association pattern” (EAP) and provides an empirical estimate of its significance, and (ii) evaluated the effect of fitting known risk variants as covariates in the eQTL analysis following Nica et al. (2010). We applied both approaches to celiac disease (CE) and rheumatoid arthritis (RA) and the second one to type one diabetes (T1D), multiple sclerosis (MS), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS) and psoriasis (PSO). Results: We detected > 16000 significant cis-eQTL, with a degree of sharing between cell types ranging from 38 to 90% highlighting the utility of our multi-tissue panel. GWAS variants were drivers of ciseQTL effects across the different tissues in 399 tests (23.6%), mostly in CD4 cells, and pinpointing 64 new gene-disease associations (3.7%). The number of shared loci and shared eQTL were highly correlated (rho=0.66).RA and SLE showed the highest degree of sharing. Conclusions: We identified new potential candidate genes for IMIDs and characterized pleiotropic effects through ciseQTL mapping in GWAS loci. These findings could shed a light on IMIDs pathogenesis and co-occurrence. Latest results will be presented. [less ▲]

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See detailHigher male than female recombination rate in cattle is controlled by genetic variants effective in both sexes
Kadri, Naveen Kumar ULg; Harland, Chad ULg; Coppieters, Wouter ULg et al

Poster (2015, May 05)

We herein study genetic recombination in three dairy cattle populations from France, New-Zealand and the Netherlands. We apply a new phasing algorithm extracting familial information suited for large half ... [more ▼]

We herein study genetic recombination in three dairy cattle populations from France, New-Zealand and the Netherlands. We apply a new phasing algorithm extracting familial information suited for large half-sib families to reconstruct haplotypes and detect cross-overs (CO). The software is robust to genotyping and map errors. We identify more than 2,000,000 CO events in sperm cells transmitted by 3008 sires to 94,603 offspring, and more than 500,000 CO events in oocytes transmitted by 11,497 cows to 25,390 offspring. When measured in identical family structures, the average number of CO in males (24.0) was found to be larger than in females (21.8). In males, recombination rates were higher closer to telomeres whereas in females, recombination rates dropped at both centromeres and telomeres (probably as a result of lower informativity). The heritability of the global recombination rate (GRR) was close to 0.20 in males and to 0.08 in females. Genetic correlation ranged from 0.38 to 0.69 depending on the population, indicating that shared variants are influencing GRR in both genders. Haplotype-based genome-wide association studies revealed four genome-wide significant QTL, including two previously identified ones (involving REC8 and RNF212). For all QTLs, there was a positive correlation between haplotype effects across sexes, ranging from 0.35 to 0.68. We selected two reference panels of respectively 122 and 215 bulls sequenced at cover > 15x to impute variants in the New-Zealand and French populations. All variants identified by next-generating sequencing in 5 Mb windows encompassing the QTL peaks were imputed with Beagle in order to perform a sequence-based association study. For three QTLs, we identified missense mutations in genes known to be involved in meiosis among the most significantly associated variants. These variants were perfectly associated with the haplotypes underlying the QTL effects. The variant identified in RNF212 had already been reported, whereas missense mutations in MLH3 (N408S) and HFM1 (S1189L) are new findings. Surprisingly, variants previously identified in REC8 did not capture the QTL effect whereas variants in RNF212B, PPP1R3E, BCL2L2, HOMEZ and PABPN1 had much stronger association with the phenotype. The three missense mutations were significant in both genders with two of them accounting for approximately 10% of the genetic variance in males (the allelic substitution effect being approximately equal to one additional CO per genome). Our results are very different from reports of recombination in other species. For instance, in human, recombination rate is higher in females, distinct variants affect recombination rate in males and females and the genetic correlation is close to 0 whereas in cattle, we observed a higher recombination rate in males controlled by shared variants effective in both sexes. [less ▲]

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See detailX-Linked acro-gigantism (X-LAG) due to microduplications of chromosome Xq26 : A new disorder and implications for acromegaly
Trivellin, G; Daly, AF; Faucz, FR et al

in Abstract book - ENDO 2015 (2015, March)

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See detailScanning the genome for QTL affecting the recombination process in the male and female cattle germline
Kadri, Naveen Kumar ULg; Harland, Chad ULg; Coppieters, Wouter ULg et al

Poster (2015, February)

We herein study genetic recombination in three dairy cattle population from France, New-Zealand and The Netherlands. We apply a new phasing algorithm extracting familial information suited for large half ... [more ▼]

We herein study genetic recombination in three dairy cattle population from France, New-Zealand and The Netherlands. We apply a new phasing algorithm extracting familial information suited for large half-sib families to reconstruct haplotypes and detect cross-overs. The software is robust to genotyping errors and map errors (genome builts still contain errors for non-model organisms). We identify more than 2,000,000 cross-over events in sperm cells transmitted by 2942 sires to 94,049 offspring, and more than 500,000 cross-over events in oocytes transmitted by 10,943 cows to 23,850 offspring. The estimated number of cross-overs per gamete and its accuracy were influenced by the family structure (number of offsprings, parents and grand-parents genotyped). The average number of cross-overs in males (24.0) was larger than in females (21.8), even after correction for family structure. In males, recombination rates were higher closer to telomeres whereas in females, recombination rates dropped at both centromeres and telomeres (probably as a result of lower informativity). The heritability of the global recombination rate was close to 0.20 in males and to 0.10 in females and the genetic correlation was ~0.70, indicating that common genes are influencing both traits. Genome-wide association studies clearly confirmed QTL located close to REC8 and RNF212 in males. The QTL associated to REC8 was also detected in females and there was a positive correlation between QTL effects in males and females. The QTL associated to REC8 accounted for ~10% of the genetic variance in both males and females. [less ▲]

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See detailLordose et/ou xyphose chez le porc : mise à l’épreuve de l’hypothèse héréditaire
Laitat, Martine ULg; Veillat, Emilie; Van Cauwenberge, Henry et al

Poster (2015, February)

Lordosis and/or kyphosis, also called ”dipped shoulder” or ”humpy‐back” is sporadically observed in growing pigs. This condition is characterized by a thoracic and/or lumbar spinal deformity ... [more ▼]

Lordosis and/or kyphosis, also called ”dipped shoulder” or ”humpy‐back” is sporadically observed in growing pigs. This condition is characterized by a thoracic and/or lumbar spinal deformity. Pathomorphologically, it may be comparable with Scheuermann’s kyphosis in man and so constitutes a spontaneous model for this humane kyphosis of the thoracic or thoracolumbar spine. In pigs, this condition may decrease the value of carcasses, making deboning efforts challenging. Three major and non‐exclusive hypotheses formulated to explain these back deformations are nutrition, intrauterine viral infection and inherited predisposition. The objective of the present study was to test the latter and, if possible, to identify a locus (some loci) associated with the affection. Forty‐eight pigs were included in this case‐control study. Based on a clinical examination and/or on a measure of the degree of spinal deformity, 25 pigs classified as affected were compared to 23 pigs considered as normal. A whole genome Single Nucleotide Polymorphism (SNP) analysis was performed using a 50,000 SNP array. DNA from forty‐seven samples (tail tissue or blood) was extracted while one sample was eliminated because of its poor quality. After applying quality controls, 40 pigs and 57,838 SNPs (on a total of 62,163) remained for further analysis. One SNP (ASGA0090747) located on Sus scrofa chromosome SSC8 crossed the genome‐wide significant threshold and is thus suspected of being associated with the lordosis and/or kyphosis phenotype. These results seem to confirm the hereditary hypothesis. Further investigations are however needed to confirm the suspected association. [less ▲]

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See detailHigh-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis.
Goyette, Philippe; Boucher, Gabrielle; Mallon, Dermot et al

in Nature Genetics (2015), 47(2), 172-9

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major ... [more ▼]

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD. [less ▲]

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See detailGenome-Wide Copy Number Variation Scan Identifies Complement Component C4 as Novel Susceptibility Gene for Crohn's Disease.
Cleynen, Isabelle; Konings, Peter; Robberecht, Caroline et al

in Inflammatory bowel diseases (2015)

BACKGROUND: The genetic component of Crohn's disease (CD) is well known, with 140 susceptibility loci identified so far. In addition to single nucleotide polymorphisms typically studied in genome-wide ... [more ▼]

BACKGROUND: The genetic component of Crohn's disease (CD) is well known, with 140 susceptibility loci identified so far. In addition to single nucleotide polymorphisms typically studied in genome-wide scans, copy number variation is responsible for a large proportion of human genetic variation. METHODS: We performed a genome-wide search for copy number variants associated with CD using array comparative genomic hybridization. One of the found regions was validated independently through real-time PCR. Serum levels of the found gene were measured in patients and control subjects. RESULTS: We found copy number differences for the C4S and C4L gene variants of complement component C4 in the central major histocompatibility complex region on chromosome 6p21. Specifically, we saw that CD patients tend to have lower C4L and higher C4S copies than control subjects (P = 5.00 x 10 and P = 9.11 x 10), which was independent of known associated classical HLA I and II alleles (P = 7.68 x 10 and P = 6.29 x 10). Although C4 serum levels were not different between patients and control subjects, the relationship between C4 copy number and serum level was different for patients and control subjects with higher copy numbers leading to higher serum concentrations in control subjects, compared with CD patients (P < 0.001). CONCLUSIONS: C4 is part of the classical activation pathway of the complement system, which is important for (auto)immunity. Low C4L or high C4S copy number, and corresponding effects on C4 serum level, could lead to an exaggerated response against infections, possibly leading to (auto)immune disease. [less ▲]

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See detailLINKPHASE3: an improved pedigree-based phasing algorithm robust to genotyping and map errors.
Druet, Tom ULg; Georges, Michel ULg

in Bioinformatics (Oxford, England) (2015), 31(10), 1677-9

Many applications in genetics require haplotype reconstruction. We present a phasing program designed for large half-sibs families (as observed in plant and animals) that is robust to genotyping and map ... [more ▼]

Many applications in genetics require haplotype reconstruction. We present a phasing program designed for large half-sibs families (as observed in plant and animals) that is robust to genotyping and map errors. We demonstrate that it is more efficient than previous versions and other programs, particularly in the presence of genotyping errors. AVAILABILITY AND IMPLEMENTATION: The software LINKPHASE3 is included in the PHASEBOOK package and can be freely downloaded from www.giga.ulg.ac.be/jcms/prod_381171/software. The package is written in FORTRAN and contains source codes. A manual is provided with the package. CONTACT: tom.druet@ulg.ac.be SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. [less ▲]

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See detailExperimental evaluation does not reveal a direct effect of microRNA from the callipyge locus on DLK1 expression.
Cheng, Huijun ULg; Xu, Xuewen; Hadfield, Tracy et al

in BMC genomics (2014), 15

BACKGROUND: Polar overdominance at the ovine callipyge (CLPG) locus involves the post-transcriptional trans-inhibition of DLK1 in skeletal muscle of CLPG/CLPG sheep. The abundant maternally expressed ... [more ▼]

BACKGROUND: Polar overdominance at the ovine callipyge (CLPG) locus involves the post-transcriptional trans-inhibition of DLK1 in skeletal muscle of CLPG/CLPG sheep. The abundant maternally expressed microRNAs (miRNAs) mapping to the imprinted DLK1-GTL2 domain are prime candidate mediators of this trans-effect. RESULTS: We have tested the affinity of 121 miRNAs processed from this locus for DLK1 by co-transfecting COS1 cells with a vector expressing the full-length ovine DLK1 with corresponding mimic miRNAs. None of the tested miRNAs was able to down regulate DLK1 to the extent observed in vivo. CONCLUSIONS: This suggests that other factors, with or without these miRNAs, are involved in mediating the observed trans-effect. [less ▲]

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See detailSelection in action: dissecting the molecular underpinnings of the increasing muscle mass of Belgian Blue Cattle
Druet, Tom ULg; Ahariz, Naïma ULg; Cambisano, Nadine ULg et al

Conference (2014, October 17)

Belgian Blue cattle are famous for their exceptional muscular development or “double-muscling”. This defining feature emerged following the fixation of a loss-of-function variant in the myostatin gene in ... [more ▼]

Belgian Blue cattle are famous for their exceptional muscular development or “double-muscling”. This defining feature emerged following the fixation of a loss-of-function variant in the myostatin gene in the eighties. Since then, sustained selection has further increased muscle mass of Belgian Blue animals to a comparable extent. In the present paper, we study the genetic determinants of this second wave of muscle growth. A scan for selective sweeps did not reveal the recent fixation of another allele with major effect on muscularity. However, a genome-wide association study identified two genome-wide significant and three suggestive QTLs affecting specific muscle groups and jointly explaining 8-21% of the heritability. The top two QTL are caused by presumably recent mutations on unique haplotypes that have rapidly risen in frequency in the population. While one appears on its way to fixation, the ascent of the other is compromised as the underlying MRC2 mutation causes crooked tail syndrome in homozygotes. Genomic prediction models indicate that the residual additive variance is largely polygenic. Contrary to complex traits in humans which have a near-exclusively polygenic architecture, muscle mass in beef cattle (as other production traits under directional selection), appears to be controlled by (i) a handful of recent mutations with large effect that rapidly sweep through the population, and (ii) a large number of presumably older variants with very small effects that rise slowly in the population (polygenic adaptation). [less ▲]

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See detailPhenotyping Belgian Blue cattle for their susceptibility to psoroptic mange
Abos, Romain ULg; Coussé, Annelies; Sarre, Charlotte et al

Poster (2014, October 17)

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See detailPedigree-based haplotype reconstruction, identification of cross-overs and detection of map and genotyping errors using PHASEBOOK
Druet, Tom ULg; Georges, Michel ULg

Conference (2014, August 22)

Haplotype reconstruction is important in many applications in animal genomics. In livestock species, thanks to the availability of large half-sibs families and genotyped relatives, phasing methods can ... [more ▼]

Haplotype reconstruction is important in many applications in animal genomics. In livestock species, thanks to the availability of large half-sibs families and genotyped relatives, phasing methods can rely on strong familial information and results in families with more than 10 offspring are very accurate. However, most methods are sensitive to genotyping and map errors which will be more common with next generation sequencing data. Such problems are particularly important when studying recombination rate as we plan to do in the near future. We herein describe a novel algorithm which is robust to genotyping errors and which can identify errors in marker maps. Using a large dairy cattle data set genotyped with high-density genotyping arrays, we show that the novel algorithm strongly reduces the occurrence of spurious cross-overs due to different sources of errors, and identifies map errors for most of the bovine autosomes. The implemented version is still experimental and further research will be conducted to characterize the novel method (including simulations) and to fully describe the identified map errors. [less ▲]

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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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