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See detailAnti-Tumor Necrosis Factor Therapy Restores Peripheral Blood B-cell Subsets and CD40 Expression in Inflammatory Bowel Diseases.
Li, Zhe; Vermeire, Severine; Bullens, Dominique et al

in Inflammatory Bowel Diseases (2015), 21(12), 2787-96

BACKGROUND: Anti-tumor necrosis factor (TNF) therapy has become a standard therapy for severe inflammatory bowel diseases (IBD), but its effect on B lymphocytes is largely unexplored. In this study we ... [more ▼]

BACKGROUND: Anti-tumor necrosis factor (TNF) therapy has become a standard therapy for severe inflammatory bowel diseases (IBD), but its effect on B lymphocytes is largely unexplored. In this study we investigated peripheral blood B cells, B-cell subsets, and CD40 expression in patients with IBD before and during anti-TNF therapy with infliximab (IFX). METHODS: Blood was taken from healthy controls (n = 52) and patients with active IBD before (n = 46) and/or during anti-TNF therapy (n = 55). B-cell markers were detected by immunofluorescent staining and FACS analysis. Patients were classified as responders or nonresponders to anti-TNF therapy. RESULTS: We found a numerical deficiency of circulating CD19 B cells, a lower activation state (CD40 expression) and lower proportions of CD5 B cells and IgMIgDCD27 preswitched memory cells among B cells in active patients with IBD before IFX therapy compared with healthy controls. IFX treatment increased CD19 B-cell numbers as well as the proportions of named B-cell subsets in responders but not in nonresponders. IFX more effectively upregulated CD40 expression in responders than in nonresponders. Restoration of B cells correlated with the biological response to therapy (C-reactive protein). Trough serum levels of IFX correlated with the number of B cells during therapy. CONCLUSIONS: A lower number of circulating B cells, a low CD40 expression, and a decrease in the proportion of CD5 and in the preswitched memory subset characterize active IBD. Restoration of these abnormalities correlates with the clinical response to anti-TNF therapy. The mechanism for this effect on B cells should be further explored. [less ▲]

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See detailSpecific members of the predominant gut microbiota predict pouchitis following colectomy and IPAA in UC.
Machiels, Kathleen; Sabino, Joao; Vandermosten, Leen et al

in Gut (2015)

OBJECTIVE: Pouchitis is the most common complication after colectomy with ileal pouch-anal anastomosis (IPAA) for UC and the risk is the highest within the 1st year after surgery. The pathogenesis is not ... [more ▼]

OBJECTIVE: Pouchitis is the most common complication after colectomy with ileal pouch-anal anastomosis (IPAA) for UC and the risk is the highest within the 1st year after surgery. The pathogenesis is not completely understood but clinical response to antibiotics suggests a role for gut microbiota. We hypothesised that the risk for pouchitis can be predicted based on the faecal microbial composition before colectomy. DESIGN: Faecal samples from 21 patients with UC undergoing IPAA were prospectively collected before colectomy and at predefined clinical visits at 1 month, 3 months, 6 months and 12 months after IPAA. The predominant microbiota was analysed using community profiling with denaturing gradient gel electrophoresis followed by quantitative real-time PCR validation. RESULTS: Cluster analysis before colectomy distinguished patients with pouchitis from those with normal pouch during the 1st year of follow-up. In patients developing pouchitis, an increase of Ruminococcus gnavus (p<0.001), Bacteroides vulgatus (p=0.043), Clostridium perfringens (p=0.011) and a reduction of two Lachnospiraceae genera (Blautia (p=0.04), Roseburia (p=0.008)) was observed. A score combining these five bacterial risk factors was calculated and presence of at least two risk factors showed a sensitivity and specificity of 100% and 63.6%, respectively. CONCLUSIONS: Presence of R. gnavus, B. vulgatus and C. perfringens and absence of Blautia and Roseburia in faecal samples of patients with UC before surgery is associated with a higher risk of pouchitis after IPAA. Our findings suggest new predictive and therapeutic strategies in patients undergoing colectomy with IPAA. [less ▲]

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See detailFramework for the Integration of Genomics, Epigenomics and Transcriptomics in Complex Diseases.
Pineda, Silvia; Gomez-Rubio, Paulina; Picornell, Antonio et al

in Human Heredity (2015), 79(3-4), 124-36

OBJECTIVES: Different types of '-omics' data are becoming available in the post-genome era; still a single -omics assessment provides limited insights to understand the biological mechanism of complex ... [more ▼]

OBJECTIVES: Different types of '-omics' data are becoming available in the post-genome era; still a single -omics assessment provides limited insights to understand the biological mechanism of complex diseases. Genomics, epigenomics and transcriptomics data provide insight into the molecular dysregulation of neoplastic diseases, among them urothelial bladder cancer (UBC). Here, we propose a detailed analytical framework necessary to achieve an adequate integration of the three sets of -omics data to ultimately identify previously hidden genetic mechanisms in UBC. METHODS: We built a multi-staged framework to study possible pair-wise combinations and integrated the data in three-way relationships. SNP genotypes, CpG methylation levels and gene expression levels were determined for a total of 70 individuals with UBC and with fresh tumour tissue available. RESULTS: We suggest two main hypothesis-based scenarios for gene regulation based on the -omics integration analysis, where DNA methylation affects gene expression and genetic variants co-regulate gene expression and DNA methylation. We identified several three-way trans-association 'hotspots' that are found at the molecular level and that deserve further studies. CONCLUSIONS: The proposed integrative framework allowed us to identify relationships at the whole-genome level providing some new biological insights and highlighting the importance of integrating -omics data. [less ▲]

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See detailTrough concentrations of infliximab guide dosing for patients with inflammatory bowel disease.
Vande Casteele, Niels; Ferrante, Marc; Van Assche, Gert et al

in Gastroenterology (2015), 148(7), 1320-93

BACKGROUND & AIMS: Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based on ... [more ▼]

BACKGROUND & AIMS: Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based on therapeutic drug monitoring increases rate of remission and whether continued concentration-based dosing is superior to clinically based dosing of infliximab for maintaining remission in patients with CD and UC. METHODS: We performed a 1-year randomized controlled trial at a tertiary referral center, including 263 adults (178 with CD and 85 with UC) with stable responses to maintenance infliximab therapy. Doses were escalated or reduced using an algorithm to reach a target trough concentration (TC) of 3-7 mug/mL in all patients (optimization phase). Patients were randomly assigned (1:1) to groups that received infliximab dosing based on their clinical features (n = 123) or continued dosing based on TCs (n = 128) (maintenance phase). The primary end point was clinical and biochemical remission at 1 year after the optimization phase. RESULTS: At screening, 115 of 263 patients had a TC of infliximab of 3-7 mug/mL (43.7%). Of 76 patients with TCs <3 mug/mL, 69 patients (91%) achieved TCs of 3-7 mug/mL after dose escalation. This resulted in a higher proportion of CD patients in remission than before dose escalation (88% vs 65%; P = .020) and a decrease in the median concentration of C-reactive protein, compared with before the dose increase (3.2 vs 4.3 mg/L; P < .001); these changes were not observed in patients with UC. Of 72 patients with TCs >7 mug/mL, 67 patients (93%) achieved TCs of 3-7 mug/mL after dose reduction. This resulted in a 28% reduction in drug cost from before dose reduction (P < .001). Sixty-six percent of patients whose dosing was based on clinical features and 69% whose dosing was based on TC achieved remission, the primary end point (P = .686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%) (P = .018). CONCLUSIONS: Targeting patients' infliximab TCs to 3-7 mug/mL results in a more efficient use of the drug. After dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 year, but was associated with fewer flares during the course of treatment. ClinicalTrialsRegister.eu number: 2011-002061-38. [less ▲]

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See detailStatistical Analysis of High-Dimensional Genetic Data in Complex Traits.
Park, Taesung; Van Steen, Kristel ULg; Lou, Xiang-Yang et al

in BioMed Research International (2015), 2015

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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 detailFramework for the integration of genomics, epigenomics, and transcriptomics in complex diseases
Pineda San Juan, Silvia ULg; Gómez-Rubio, Paulina; Antoni, Picornell et al

in Human Heredity (2015)

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See detailFilter-free exhaustive odds ratio-based genome-wide interaction approach pinpoints evidence for interaction in the HLA region in psoriasis.
Grange, Laura; Bureau, Jean-Francois; Nikolayeva, Iryna et al

in BMC genetics (2015), 16(1), 11

BackgroundDeciphering the genetic architecture of complex traits is still a major challenge for human genetics. In most cases, genome-wide association studies have only partially explained the ... [more ▼]

BackgroundDeciphering the genetic architecture of complex traits is still a major challenge for human genetics. In most cases, genome-wide association studies have only partially explained the heritability of traits and diseases. Epistasis, one potentially important cause of this missing heritability, is difficult to explore at the genome-wide level. Here, we develop and assess a tool based on interactive odds ratios (IOR), Fast Odds Ratio-based sCan for Epistasis (FORCE), as a novel approach for exhaustive genome-wide epistasis search. IOR is the ratio between the multiplicative term of the odds ratio (OR) of having each variant over the OR of having both of them. By definition, an IOR that significantly deviates from 1 suggests the occurrence of an interaction (epistasis). As the IOR is fast to calculate, we used the IOR to rank and select pairs of interacting polymorphisms for P value estimation, which is more time consuming.ResultsFORCE displayed power and accuracy similar to existing parametric and non-parametric methods, and is fast enough to complete a filter-free genome-wide epistasis search in a few days on a standard computer. Analysis of psoriasis data uncovered novel epistatic interactions in the HLA region, corroborating the known major and complex role of the HLA region in psoriasis susceptibility.ConclusionsOur systematic study revealed the ability of FORCE to uncover novel interactions, highlighted the importance of exhaustiveness, as well as its specificity for certain types of interactions that were not detected by existing approaches. We therefore believe that FORCE is a valuable new tool for decoding the genetic basis of complex diseases. [less ▲]

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See detailShort-term Effect of Infliximab Is Reflected in the Clot Lysis Profile of Patients with Inflammatory Bowel Disease: A Prospective Study.
Bollen, Lize; Vande Casteele, Niels; Peeters, Miet et al

in Inflammatory bowel diseases (2015), 21(3), 570-8

BACKGROUND: Inflammatory bowel disease (IBD) is recognized as an independent risk factor for thrombosis. First, we investigate whether the concentration of fibrinolysis inhibitors is increased in patients ... [more ▼]

BACKGROUND: Inflammatory bowel disease (IBD) is recognized as an independent risk factor for thrombosis. First, we investigate whether the concentration of fibrinolysis inhibitors is increased in patients with IBD. Second, we investigate the effect of infliximab induction therapy on the hemostatic profile. METHODS: This prospective study included 103 patients with IBD starting infliximab therapy and 113 healthy controls. Plasma was collected before the first infliximab infusion (wk 0) and after induction therapy (wk 14). Patients not showing a clinical response on induction were considered as primary nonresponders. Fibrinolysis inhibitors were measured by enzyme-linked immunosorbent assay. Using a clot lysis assay, the area under the curve (global marker for coagulation/fibrinolysis), 50% clot lysis time (marker for fibrinolytic capacity), and amplitude (indicator for clot formation) were determined. RESULTS: Patients with IBD selected for infliximab treatment have higher area under the curve (median 29 [interquartile range, 20-38]) and amplitude (0.4 [0.3-0.5]) compared with healthy controls (18 [13-24] and 0.3 [0.2-0.3], respectively, P < 0.001). Primary nonresponders showed a decrease neither in inflammatory markers nor in hemostatic parameters, whereas in primary responders, a decrease in inflammatory markers was associated with a decrease in both area under the curve (29 [20-38] (wk 0) to 20 [14-28] (wk 14), P < 0.001) and amplitude (0.4 [0.3-0.5] (wk 0) to 0.3 [0.3-0.4] (wk 14), P < 0.001). CONCLUSIONS: This is the first prospective study demonstrating that the clot lysis profile differs between patients with IBD and healthy individuals. On infliximab induction treatment, this clot lysis profile normalizes in responders suggesting that infliximab treatment is advisable for patients with IBD with an activated hemostatic profile. [less ▲]

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See detailWithdrawal of Immunomodulators After Co-treatment Does Not Reduce Trough Level of Infliximab in Patients With Crohn's Disease.
Drobne, David; Bossuyt, Peter; Breynaert, Christine et al

in Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association (2015), 13(3), 514-5214

BACKGROUND & AIMS: The addition of immunomodulators increases the efficacy of maintenance therapy with infliximab for up to 1 year in patients with Crohn's disease who have not been previously treated ... [more ▼]

BACKGROUND & AIMS: The addition of immunomodulators increases the efficacy of maintenance therapy with infliximab for up to 1 year in patients with Crohn's disease who have not been previously treated with immunomodulators. However, there are questions about the effect of withdrawing immunomodulator therapy from these patients. We studied the effects of treatment with infliximab and immunomodulators (co-treatment) and then immunomodulator withdrawal on long-term outcomes of patients, as well as trough levels of infliximab and formation of anti-infliximab antibodies (ATI). METHODS: In a retrospective study with the median follow-up period of 34 months (interquartile range, 19-58 months), we analyzed data from 223 patients treated for Crohn's disease between May 1999 and December 2010 at the University Hospitals, Leuven, Belgium (65 received infliximab monotherapy, 158 received infliximab and an immunomodulator). Trough levels of infliximab and levels of ATI were measured in blood samples collected from 117 patients throughout co-treatment, as well as the time of immunomodulator withdrawal and after withdrawal. RESULTS: Patients receiving co-treatment had higher trough levels of infliximab (adjusted mean increase, 1.44-fold) than those receiving infliximab monotherapy (95% confidence interval [CI], 1.07-1.92; P = .02). A smaller percentage of patients receiving co-treatment developed ATI (35 of 158, 22%) than those receiving infliximab monotherapy (25 of 65, 38%; P = .01). Among co-treated patients, levels of infliximab remained stable after immunomodulators were withdrawn (before: 3.2 mug/mL; 95% CI, 1.6-5.8 mug/mL and after: 3.7 mug/mL; 95% CI, 1.3-6.3 mug/mL; P = .70). After withdrawal of immunomodulators, 45 of 117 patients (38%) required increasing doses of infliximab, and 21 of 117 (18%) discontinued infliximab. At the time of immunomodulator withdrawal, trough levels of infliximab and C-reactive protein were most strongly associated with response to infliximab thereafter. CONCLUSIONS: In a retrospective analysis, we confirmed that withdrawal of immunomodulators after at least 6 months (median, 13 months) of co-treatment with infliximab does not reduce the trough levels of infliximab in patients with Crohn's disease. Detectable trough levels of infliximab at the time of immunomodulator withdrawal are associated with long-term response. [less ▲]

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See detailCombining Genotype with LD-based haplotype information as input for iterative pruning principal component analysis (ipPCA) to improve population clustering
Chaichoompu, Kridsadakorn ULg; Fouladi, Ramouna ULg; Wangkumhang, Pongsakorn et al

Conference (2014, November 26)

Single Nucleotide Polymorphisms (SNPs) are commonly used to capture variations between populations and often genome-wide SNP data are pruned based on linkage disequilibrium (LD) patterns. To identify and ... [more ▼]

Single Nucleotide Polymorphisms (SNPs) are commonly used to capture variations between populations and often genome-wide SNP data are pruned based on linkage disequilibrium (LD) patterns. To identify and differentiate between subpopulations using a rich set of genetic markers, as using reduced sets of genetic markers for these purposes, can become challenging especially when similar geographic regions are involved or when spurious patterns are likely to exist. Notably, haplotype composition and the pattern of LD between markers may vary between larger populations but may also play a role within more confined geographic regions. Indeed, the structure of haplotypes in unrelated individuals can reveal useful information about genetic ancestry. Here, we use iterative pruning principal component analysis (ipPCA) [1] to identify and characterize subpopulations in an unsupervised way. Furthermore, we purpose to combine an LD-based haplotype encoding scheme with the ipPCA machinery to retrieve fine population substructures. Despite the complexities that are associated with haplotype inference, added value can be obtained when the LD structure between SNPs is exploited in the search for relevant population strata. As input data, either pruned genome-wide SNP data are used or multilocus haplotype information derived from the genome-wide SNP panel. Preliminary results indicate that ipPCA applied to pruned SNP data or ipPCA that explicitly uses multilocus information (haplotypes) give complementary information about population substructure for geographically confined populations. In fact, both methods address different aspects of population structure. [1] Intarapanich, A. et al. (2009), BMC Bioinformatics. 10: p. 382. [less ▲]

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See detailgammaMAXT: a fast multiple-testing correction algorithm
Van Lishout, François ULg; Gadaleta, Francesco ULg; Moore, Jason H. et al

in ERCIM 2014 Abstract Book (2014, November 12)

The purpose of the maxT algorithm (1993) is to control the family-wise error rate (FWER) when assessing significance of multiple tests jointly. However, the requirements in terms of computing time and ... [more ▼]

The purpose of the maxT algorithm (1993) is to control the family-wise error rate (FWER) when assessing significance of multiple tests jointly. However, the requirements in terms of computing time and memory of this procedure are proportional to the number of investigated hypothesis. The memory issue has been solved by Van Lishout’s implementation of maxT (2013), which makes the memory usage independent from the size of the dataset. This algorithm is implemented in MBMDR-3.0.3, a software that is able to identify genetic interactions, for a variety of SNP-SNP based epistasis model,s in an effective way. However, that implementation turned out to be less suitable for genome-wide interaction analysis studies, due to the prohibitive computational burden. Here, we present gammaMAXT, a novel algorithm which is part of MBMDR-4.2.2. We show that, in the abscence of interaction effects, test-statistics produced by the MB-MDR methodology follow a mixture distribution with a point mass at zero and a shifted gamma distribution for the top 10% of the strictly positive values. We show that the gammaMAXT algorithm has a power comparable to maxT and maintains FWER, but requires less computational resources and time. MBMDR-4.2.2 can be downloaded at http://www.statgen.ulg.ac.be. [less ▲]

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See detailPractical aspects of genome-wide association interaction analysis.
Gusareva, Elena ULg; Van Steen, Kristel ULg

in Human Genetics (2014), 133(11), 1343-58

Large-scale epistasis studies can give new clues to system-level genetic mechanisms and a better understanding of the underlying biology of human complex disease traits. Though many novel methods have ... [more ▼]

Large-scale epistasis studies can give new clues to system-level genetic mechanisms and a better understanding of the underlying biology of human complex disease traits. Though many novel methods have been proposed to carry out such studies, so far only a few of them have demonstrated replicable results. Here, we propose a minimal protocol for genome-wide association interaction (GWAI) analysis to identify gene–gene interactions from large-scale genomic data. The different steps of the developed protocol are discussed and motivated, and encompass interaction screening in a hypothesis-free and hypothesisdriven manner. In particular, we examine a wide range of aspects related to epistasis discovery in the context of complex traits in humans, hereby giving practical recommendations for data quality control, variant selection or prioritization strategies and analytic tools, replication and meta-analysis, biological validation of statistical findings and other related aspects. The minimal protocol provides guidelines and attention points for anyone involved in GWAI analysis and aims to enhance the biological relevance of GWAI findings. At the same time, the protocol improves a better assessment of strengths and weaknesses of published GWAI methodologies. [less ▲]

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See detailCombining genotype with allelic association as input for iterative pruning principal component analysis (ipPCA) to resolve population substructures
Chaichoompu, Kridsadakorn ULg; Fouladi, Ramouna ULg; Wangkumhang, Pongsakorn et al

Poster (2014, August 28)

Single Nucleotide Polymorphisms (SNPs) are commonly used to capture variations between populations and often genome-wide SNP data are pruned based on linkage disequilibrium (LD) patterns. Notably ... [more ▼]

Single Nucleotide Polymorphisms (SNPs) are commonly used to capture variations between populations and often genome-wide SNP data are pruned based on linkage disequilibrium (LD) patterns. Notably, haplotype composition and the pattern of LD between markers may vary between larger populations but may also play a role within more confined geographic regions. Indeed, knowledge about haplotypes in unrelated individuals can reveal useful information about genetic ancestry. Here, we use iterative pruning principal component analysis (ipPCA) [Intarapanich 2009] to identify and characterize subpopulations in an unsupervised way using a rich set of genetic markers since using reduced sets of genetic markers for these purposes can become challenging, especially when similar geographic regions are involved or when spurious patterns are likely to exist. As input data, either pruned genome-wide SNP data are used or multilocus haplotype information derived from the genome-wide SNP panel. These approaches are applied to real-life data from 4028 Vietnamese individuals [Khor 2012]. Preliminary results indicate that ipPCA applied to pruned SNP data or ipPCA that explicitly uses multilocus information (haplotypes) give complementary information about population substructure for geographically confined populations. Both methods address different aspects of population structure. In conclusion, we propose to combine an LD-based haplotype encoding scheme with the ipPCA machinery to retrieve fine population substructures. Despite the complexities that are associated with haplotype inference, added value can be obtained when the LD structure between SNPs is exploited in the search for relevant population strata. [less ▲]

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See detailGenome-Wide Association Interaction Analysis for Alzheimer’s Disease
Gusareva, Elena ULg; Carrasquillo, Minerva M.; Bellenguez, Céline et al

in Neurobiology of Aging (2014)

We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and ... [more ▼]

We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and statistical tools. The different steps of this protocol are illustrated on a real-life data application for Alzheimer's disease (AD) (2259 patients and 6017 controls from France). Particularly, in the exhaustive genome-wide epistasis screening we identified AD-associated interacting SNPs-pair from chromosome 6q11.1 (rs6455128, the KHDRBS2 gene) and 13q12.11 (rs7989332, the CRYL1 gene) (p = 0.006, corrected for multiple testing). A replication analysis in the independent AD cohort from Germany (555 patients and 824 controls) confirmed the discovered epistasis signal (p = 0.036). This signal was also supported by a meta-analysis approach in 5 independent AD cohorts that was applied in the context of epistasis for the first time. Transcriptome analysis revealed negative correlation between expression levels of KHDRBS2 and CRYL1 in both the temporal cortex (β = -0.19, p = 0.0006) and cerebellum (β = -0.23, p < 0.0001) brain regions. This is the first time a replicable epistasis associated with AD was identified using a hypothesis free screening approach. [less ▲]

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See detailLD-based haplotype encoding scheme with iterative pruning principal component analysis (ipPCA) to retrieve population substructures
Chaichoompu, Kridsadakorn ULg; Fouladi, Ramouna ULg; Wangkumhang, Pongsakorn et al

Poster (2014, April 29)

Objective To identify and differentiate between subpopulations using a rich set of genetic markers, as using reduced sets of genetic markers for these purposes can become challenging, especially when ... [more ▼]

Objective To identify and differentiate between subpopulations using a rich set of genetic markers, as using reduced sets of genetic markers for these purposes can become challenging, especially when similar geographic regions are involved or when spurious patterns are likely to exist. Method Single Nucleotide Polymorphisms (SNPs) are commonly used to capture variations between populations and often genome-wide SNP data are pruned based on linkage disequilibrium (LD) patterns. Notably, haplotype composition and the pattern of LD between markers may vary between larger populations but may also play a role within more confined geographic regions. Indeed, knowledge about haplotypes in unrelated individuals can reveal useful information about genetic ancestry. Here, we use iterative pruning principal component analysis (ipPCA) [1] to identify and characterize subpopulations in an unsupervised way. As input data, either pruned genome-wide SNP data are used (using PLINK 1.9 with the "indep-pairwise" option, window size = 100k, r2 < 0.25) or multilocus haplotype information derived from the genome-wide SNP panel (using BEAGLE 3.3.2 to infer haplotype). These approaches are applied to real-life data from 992 Thai individuals [2]. Result Preliminary results indicate that ipPCA applied to pruned SNP data or ipPCA that explicitly uses multilocus information (haplotypes) give complementary information about population substructure for geographically confined populations such as the Thai samples in this study. Both methods address different aspects of population structure. Detailed simulation studies are needed to identify the optimal scenarios for haplotype-based ipPCA. Conclusion In this work, we propose to combine an LD-based haplotype encoding scheme with the ipPCA machinery to retrieve fine population substructures. Despite the complexities that are associated with haplotype inference, added value can be obtained when the LD structure between SNPs is exploited in the search for relevant population strata. References 1. Intarapanich, A., et al., Iterative pruning PCA improves resolution of highly structured populations. BMC Bioinformatics, 2009. 10: p. 382. 2. Wangkumhang, P., et al., Insight into the peopling of Mainland Southeast Asia from Thai population genetic structure. PLoS One, 2013. 8(11): p. e79522. [less ▲]

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See detailGenome-wide association interaction analysis for Alzheimer’s disease.
Gusareva, Elena ULg; Bellenguez, C; Cuyvers, E et al

Poster (2014, January 27)

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