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See detailGenome-wide association study identifies sequence variants within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm.
Gretarsdottir, Solveig; Baas, Annette F.; Thorleifsson, G. et al

in Nature Genetics (2010)

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See detailGenome-wide association study of migraine implicates a common susceptibility variant on 8q22.1.
Anttila, Verneri; Stefansson, Hreinn; Kallela, Mikko et al

in Nature Genetics (2010), 42(10), 869-73

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular ... [more ▼]

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 x 10, odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 x 10(1)(1) (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 x 10, permuted threshold for genome-wide significance 7.7 x 10. To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine. [less ▲]

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See detailGenome-wide Determinants of Proviral Targeting, Clonal Abundance and Expression in Natural HTLV-1 Infection.
Melamed, Anat; Laydon, Daniel J.; Gillet, Nicolas ULg et al

in PLoS Pathogens (2013), 9(3), 1003271

The regulation of proviral latency is a central problem in retrovirology. We postulate that the genomic integration site of human T lymphotropic virus type 1 (HTLV-1) determines the pattern of expression ... [more ▼]

The regulation of proviral latency is a central problem in retrovirology. We postulate that the genomic integration site of human T lymphotropic virus type 1 (HTLV-1) determines the pattern of expression of the provirus, which in turn determines the abundance and pathogenic potential of infected T cell clones in vivo. We recently developed a high-throughput method for the genome-wide amplification, identification and quantification of proviral integration sites. Here, we used this protocol to test two hypotheses. First, that binding sites for transcription factors and chromatin remodelling factors in the genome flanking the proviral integration site of HTLV-1 are associated with integration targeting, spontaneous proviral expression, and in vivo clonal abundance. Second, that the transcriptional orientation of the HTLV-1 provirus relative to that of the nearest host gene determines spontaneous proviral expression and in vivo clonal abundance. Integration targeting was strongly associated with the presence of a binding site for specific host transcription factors, especially STAT1 and p53. The presence of the chromatin remodelling factors BRG1 and INI1 and certain host transcription factors either upstream or downstream of the provirus was associated respectively with silencing or spontaneous expression of the provirus. Cells expressing HTLV-1 Tax protein were significantly more frequent in clones of low abundance in vivo. We conclude that transcriptional interference and chromatin remodelling are critical determinants of proviral latency in natural HTLV-1 infection. [less ▲]

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See detailGenome-wide environmental interaction analysis using multidimensional data reduction principles to identify asthma pharmacogenetic loci in relation to corticosteroid therapy
Van Lishout, François ULg; Bessonov, Kyrylo ULg; Duan, Quingling et al

Poster (2013, October 25)

Genome-wide gene-environment (GxE) and gene-gene (GxG) interaction studies share a lot of challenges via the common genetic component they involve. GWEI studies may therefore benefit from the abundance of ... [more ▼]

Genome-wide gene-environment (GxE) and gene-gene (GxG) interaction studies share a lot of challenges via the common genetic component they involve. GWEI studies may therefore benefit from the abundance of methodologies that are available in the context of genome-wide epistasis detection methods. One of these is Model-Based Multifactor Dimensionality Reduction (MB-MDR), which does not make any assumption about the genetic inheritance model. MB-MDR involves reducing a high-dimensional GxE space to GxE factor levels that either exhibit high or low or no evidence for their association to disease outcome. In contrast to logistic regression and random forests, MB-MDR can be used to detect GxE interactions in the absence of any main effects or when sample sizes are too small to be able to model all main and GxE interaction effects. In this ongoing study, we demonstrate the opportunities and challenges of MB-MDR for genome-wide GxE interaction analysis and analyzed the difference in prebronchodilator FEV1 following 8 weeks of inhaled corticosteroid therapy, for 565 pediatric Caucasian CAMP (ages 5-12) from the SHARE project. [less ▲]

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See detailGenome-wide epistasis screening for asthma associated traits
Gusareva, Elena ULg; Huyghe, Jeroen; Van Steen, Kristel ULg

Poster (2011, August 01)

Genome-wide association (GWA) studies of asthma and associated traits have identified numerous genes. A substantial portion of the heritability of these traits remains unexplained. Some variants, not ... [more ▼]

Genome-wide association (GWA) studies of asthma and associated traits have identified numerous genes. A substantial portion of the heritability of these traits remains unexplained. Some variants, not detectable via main effects GWA study may manifest themselves only in interaction with other variants. To search for interacting genes involved in regulation of asthma associated traits (total IgE, eosinophils, FEV1, FVC, FEV1/FVC) we performed GWA epistasis screening in two family groups of asthma patients:CAMP (Childhood Asthma Management Program:814 cases and 467 trios) and CARE (Childhood Asthma Research and Education:796 cases and 338 trios) [dbGaP accession number phs000166.v1.p1.c1]. Individuals were genotyped with the Aymetrix 6.0 array. After quality control 574922 and 575010 SNPs in CAMP and CARE respectively, were tested with FBAT. No main effects genome-wide significant associations were found. We prioritized candidate pairs of SNPs for MB-MDR epistasis screening using Biofilter leading to 7632 SNPs for CAMP and 7603 SNPs for CARE. The most significant pair-wise interaction was identified between SNPs from loci 7p21.1 and 12q23.3 influencing eosinophil level in asthmatics. [less ▲]

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See detailGenome-wide epistasis screening for Crohns’ disease
Gusareva, Elena ULg; Van Steen, Kristel ULg

Poster (2011, September 19)

Genome-wide association (GWA) studies of Crohn's disease have identified numerous genes. However, a substantial portion of the heritability of this disease remains unexplained. Some gene variants, not ... [more ▼]

Genome-wide association (GWA) studies of Crohn's disease have identified numerous genes. However, a substantial portion of the heritability of this disease remains unexplained. Some gene variants, not detectable via main effects GWA study, may manifest themselves only in interaction with other variants. To search for interacting genes involved in the regulation of Crohn's disease, we performed GWA epistasis screening in a large human cohort (1851 cases/2938 controls) belonging to the Wellcome Trust Case Control Consortium (WTCCC). All subjects were genotyped with the GeneChip 500K Mapping Array Set (Affymetrix chip). SNPs that passed our quality control (359,479 SNPs) were processed in Biofilter (a software package that looks for candidate epistatic genes contributing to disease risk) giving rise to 14,185 SNPs. Subsequent MB-MDR epistasis screening discovered four pairs of interacting SNPs on chromosome 4q35.1 and eight pairs on chromosome 11q23.2. The identified pairs of SNPs were confirmed with synergy-based measures. Notably, despite their mapping to the same genomic regions, the interacting SNPs were not in LD (r^2 < 0.5). Our findings support the idea of close chromosomal localization of two pairs of interacting genes that are involved in development of Crohn's disease. [less ▲]

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See detailA genome-wide linkage study of individuals with high scores on NEO personality traits
Amin, Najaf; Schuur, M.; Gusareva, Elena ULg et al

in Molecular Psychiatry (2011)

The NEO-Five-Factor Inventory divides human personality traits into five dimensions: neuroticism, extraversion, openness, conscientiousness and agreeableness. In this study, we sought to identify regions ... [more ▼]

The NEO-Five-Factor Inventory divides human personality traits into five dimensions: neuroticism, extraversion, openness, conscientiousness and agreeableness. In this study, we sought to identify regions harboring genes with large effects on the five NEO personality traits by performing genome-wide linkage analysis of individuals scoring in the extremes of these traits ( > 90th percentile). Affected-only linkage analysis was performed using an Illumina 6K linkage array in a family-based study, the Erasmus Rucphen Family study. We subsequently determined whether distinct, segregating haplotypes found with linkage analysis were associated with the trait of interest in the population. Finally, a dense single-nucleotide polymorphism genotyping array (Illumina 318K) was used to search for copy number variations (CNVs) in the associated regions. In the families with extreme phenotype scores, we found significant evidence of linkage for conscientiousness to 20p13 (rs1434789, log of odds (LOD) = 5.86) and suggestive evidence of linkage (LOD > 2.8) for neuroticism to 19q, 21q and 22q, extraversion to 1p, 1q, 9p and12q, openness to 12q and 19q, and agreeableness to 2p, 6q, 17q and 21q. Further analysis determined haplotypes in 21q22 for neuroticism (P-values = 0.009, 0.007), in 17q24 for agreeableness (marginal P-value = 0.018) and in 20p13 for conscientiousness (marginal P-values = 0.058, 0.038) segregating in families with large contributions to the LOD scores. No evidence for CNVs in any of the associated regions was found. Our findings imply that there may be genes with relatively large effects involved in personality traits, which may be identified with next-generation sequencing techniques. [less ▲]

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See detailGenome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci.
Franke, Andre; McGovern, Dermot P B; Barrett, Jeffrey C et al

in Nature Genetics (2010), 42(12), 1118-25

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in ... [more ▼]

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 x 10). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease. [less ▲]

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See detailGenomic Association Screening Methodology for High-Dimensional and Complex Data Structures: Detecting n-Order Interactions
Mahachie John, Jestinah ULg

Doctoral thesis (2012)

We developed a data-mining method, Model-Based Multifactor Dimensionality Reduction (MB-MDR) to detect epistatic interactions for different types of traits. MB-MDR enables the fast identification of gene ... [more ▼]

We developed a data-mining method, Model-Based Multifactor Dimensionality Reduction (MB-MDR) to detect epistatic interactions for different types of traits. MB-MDR enables the fast identification of gene-gene interactions among 1000nds of SNPs, without the need to make restrictive assumptions about the genetic modes of inheritance. This thesis primarily focused on applying Model-Based Multifactor Dimensionality Reduction for quantitative traits, its performance and application to a variety of data problems. We carried out several simulation studies to evaluate quantitative MB-MDR in terms of power and type I error, when data are noisy, non-normal or skewed and when important main effects are present. Firstly, we assessed the performance of MB-MDR in the presence of noisy data. The error sources considered were missing genotypes, genotyping error, phenotypic mixtures and genetic heterogeneity. Results from this study showed that MB-MDR is least affected by presence of small percentages of missing data and genotyping errors but much affected in the presence of phenotypic mixtures and genetic heterogeneity. This is in line with a similar study performed for binary traits. Although both Multifactor Dimensionality Reduction (MDR) and MB-MDR are data reduction techniques with a common basis, their ways of deriving significant interactions are substantially different. Nevertheless, effects on power of introducing error sources were quite similar. Irrespective of the trait under consideration, epistasis screening methodologies such as MB-MDR and MDR mainly suffer from the presence of phenotypic mixtures and genetic heterogeneity. Secondly, we extensively addressed the issue of adjusting for lower-order genetic effects during epistasis screening, using different adjustment strategies for SNPs in the functional SNP-SNP interaction pair, and/or for additional important SNPs. Since, in this thesis, we restrict attention to 2-locus interactions only, adjustment for lower-order effects always (and only) implies adjustment for main genetic effects. Unfortunately most data dimensionality reduction techniques based on MDR do not explicitly require that lower-order effects are included in the ‘model’ when investigating higher-order effects (a prerequisite for most traditional, especially regression-based, methods). However, epistasis results may be hampered by the presence of significant lower-order effects. Results from this study showed hugely increased type I errors when main effects were not taken into account or were not properly accounted for. We observed that additive coding (the most commonly used coding in practice) in main effects adjustment does not remove all of the potential main effects that deviate from additive genetic variance. In addition, also adjusting for main effects prior to MB-MDR (via a regression framework), whatever coding is adopted, does not control type I error in all scenarios. From this study, we concluded that correction for lower-order effects should preferentially be done via codominant coding, to reduce the chance of false positive epistasis findings. The recommended way of performing an MB-MDR epistasis screening is to always adjust the analysis for lower-order effects of the SNPs under investigation, “on-the-fly”. This correction avoids overcorrection for other SNPs, which are not part of the interacting SNP pair under study. Thirdly, we assessed the cumulative effect of trait deviations from normality and homoscedasticity on the overall performance of quantitative MB-MDR to detect 2-locus epistasis signals in the absence of main effects. Although MB-MDR itself is a non-parametric method, in the sense that no assumptions are made regarding genetic modes of inheritance, the data reduction part in MB-MDR relies on association tests. In particular, for quantitative traits, the default MB-MDR way is to use the Student’s t-test (steps 1 and 2 of MB-MDR). Also when correcting for lower-order effects during quantitative MB-MDR analysis, we intrinsically maneuver within a regression framework. Since the Student’s t-statistic is the square root of the ANOVA F-statistic. Hence, along these lines, for MB-MDR to give valid results, ANOVA assumptions have to be met. Therefore, we simulated data from normal and non-normal distributions, with constant and non-constant variances, and performed association tests via the student’s t-test as well as the unequal variance t-test, commonly known as the Welch’s t-test. At first somewhat surprising, the results of this study showed that MB-MDR maintains adequate type I errors, irrespective of data distribution or association test used. On the other hand, MB-MDR give rise to lower power results for non-normal data compared to normal data. With respect to the association tests used within MB-MDR, in most cases, Welch’s t-test led to lower power compared to student’s t-test. To maintain the balance between power and type I error, we concluded that when performing MB-MDR analysis with quantitative traits, one ideally first rank-transforms traits to normality and then applies MB-MDR modeling with Student’s t-test as choice of association test. Clearly, before embarking on using a method in practice, there is a need to extensively check the applicability of the method to the data at hand. This is a common practice in biostatistics, but often a forgotten standard operating procedure in genetic epidemiology, in particular in GWAI studies. In addition to the presentation of extensive simulation studies, we also presented some MB-MDR applications to real-life data problems. These analyses involved MB-MDR analyses on quantitative as well as binary complex disease traits, primarily in the context of asthma/allergy and Crohn’s disease. In two of the presented analyses, MB-MDR confirmed logistic regression and transmission disequilibrium test (TDT) results. Part of the aforementioned methodological developments was initiated on the basis of observations of MB-MDR behavior on real-life data. Both the practical and theoretical components of this thesis confirm our belief in the potential of MB-MDR as a promising and versatile tool for the identification of epistatic effects, irrespective of the design (family-based or unrelated individuals) and irrespective of the targeted disease trait (binary, continuous, censored, categorical, multivariate). A thorough characterization of the different faces of MB-MDR this versatility gives rise to is work in progress. [less ▲]

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See detailGenomic breeding value estimation using genetic markers, inferredancestral haplotypes, and the genomic relationship matrix
de Roos, A. P. W.; Schrooten, C.; Druet, Tom ULg

in Journal of Dairy Science (2011), 94(9), 4708-4714

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See detailGenomic deletions of OFD1 account for 23% of oral-facial-digital type 1 syndrome after negative DNA sequencing.
Thauvin-Robinet, Christel; Franco, Brunella; Saugier-Veber, Pascale et al

in Human Mutation (2008), 30(2), 320-9

Oral-facial-digital type I syndrome (OFDI) is characterised by an X-linked dominant mode of inheritance with lethality in males. Clinical features include facial dysmorphism with oral, dental and distal ... [more ▼]

Oral-facial-digital type I syndrome (OFDI) is characterised by an X-linked dominant mode of inheritance with lethality in males. Clinical features include facial dysmorphism with oral, dental and distal abnormalities, polycystic kidney disease and central nervous system malformations. Considerable allelic heterogeneity has been reported within the OFD1 gene, but DNA bi-directional sequencing of the exons and intron-exon boundaries of the OFD1 gene remains negative in more than 20% of cases. We hypothesized that genomic rearrangements could account for the majority of the remaining undiagnosed cases. Thus, we took advantage of two independent available series of patients with OFDI syndrome and negative DNA bi-directional sequencing of the exons and intron-exon boundaries of the OFD1 gene from two different European labs: 13/36 cases from the French lab; 13/95 from the Italian lab. All patients were screened by a semiquantitative fluorescent multiplex method (QFMPSF) and relative quantification by real-time PCR (qPCR). Six OFD1 genomic deletions (exon 5, exons 1-8, exons 1-14, exons 10-11, exons 13-23 and exon 17) were identified, accounting for 5% of OFDI patients and for 23% of patients with negative mutation screening by DNA sequencing. The association of DNA direct sequencing, QFMPSF and qPCR detects OFD1 alteration in up to 85% of patients with a phenotype suggestive of OFDI syndrome. Given the average percentage of large genomic rearrangements (5%), we suggest that dosage methods should be performed in addition to DNA direct sequencing analysis to exclude the involvement of the OFD1 transcript when there are genetic counselling issues. [less ▲]

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See detailGenomic Divergence among Sindbis Virus Strains
Rentier-Delrue, Françoise ULg; Young, N. A.

in Virology (1980), 106

Antigenic variants of the alphavirus Sindbis strains have been isolated from the Paleartic, Ethiopian, Oriental, and Australian zoogeographic regions. The genome of these variants were analyzed for ... [more ▼]

Antigenic variants of the alphavirus Sindbis strains have been isolated from the Paleartic, Ethiopian, Oriental, and Australian zoogeographic regions. The genome of these variants were analyzed for homology by hybridization of virion RNAs to double-stranded RNAs isolated from infected cells. Under nonstringent conditions (Tm-55°) the RNA of Oriental-Australian strains showed only 35 to 51% nucleotide sequence homology with the RNAs of the Paleartic-Ethiopian strains although homology was essentially complete among isolates within the Oriental and Australian regions and among isolates within the Paleartic and Ethiopian regions. Under more stringent conditions (Tm-26°), nucleotide sequence differences of 2 to 45% were detected among the RNAs of virus strains from geographically distant localities within each of these two major zoogeographic subdivisions. Year of isolation, passage histoty and vertebrate or invertebrate host of origin were not major determinants of sequence heterology. The hypothesis that ancestral Sindbis virus became separated by geographic barriers and evolved into two distinct types is presented. Further divergent evolution has obviously occurred wihin each of these types. [less ▲]

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See detailGenomic Diversity among Bovine Herpesvirus 4 Field Isolates
Bublot, M.; Wellemans, G.; Van Bressem, M. F. et al

in Archives of Virology (1991), 116(1-4), 1-18

Twenty-eight Belgian field isolates of bovine herpesvirus 4 (BHV-4) coming from a variety of clinical diseases have been studied by restriction analysis and Southern blot hybridization. The unique central ... [more ▼]

Twenty-eight Belgian field isolates of bovine herpesvirus 4 (BHV-4) coming from a variety of clinical diseases have been studied by restriction analysis and Southern blot hybridization. The unique central part of the genome was very well conserved among strains; only one variation in a restriction site was detected in 3 isolates which contain an additional EcoRI site also present in the LVR 140 strain; three regions in the unique part of the genome varied in size, one of these was highly variable. The polyrepetitive fragments (prDNAs) situated in tandem at both genomic ends were also variable in size; most of the isolates exhibited prDNA units of one size (major prDNA) and some of them also contained prDNA units having a different size and present in a lower amount (minor prDNA) than the major prDNA. Other isolates possessed two major prDNAs of different sizes which were both present in the same genome. The left junction fragment between the unique and the repeated sequences was also highly variable. No relationship could be established between the restriction pattern and the origin of the isolates; patterns of isolates coming from the same herd were similar except in one case. This study provides a view of the genome variability existing between BHV-4 field isolates. [less ▲]

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See detailGenomic evidence for ameiotic evolution in the bdelloid rotifer Adineta vaga.
Flot, Jean-Francois; Hespeels, Boris; Li, Xiang et al

in Nature (2013), 500(7463), 453-7

Loss of sexual reproduction is considered an evolutionary dead end for metazoans, but bdelloid rotifers challenge this view as they appear to have persisted asexually for millions of years. Neither male ... [more ▼]

Loss of sexual reproduction is considered an evolutionary dead end for metazoans, but bdelloid rotifers challenge this view as they appear to have persisted asexually for millions of years. Neither male sex organs nor meiosis have ever been observed in these microscopic animals: oocytes are formed through mitotic divisions, with no reduction of chromosome number and no indication of chromosome pairing. However, current evidence does not exclude that they may engage in sex on rare, cryptic occasions. Here we report the genome of a bdelloid rotifer, Adineta vaga (Davis, 1873), and show that its structure is incompatible with conventional meiosis. At gene scale, the genome of A. vaga is tetraploid and comprises both anciently duplicated segments and less divergent allelic regions. However, in contrast to sexual species, the allelic regions are rearranged and sometimes even found on the same chromosome. Such structure does not allow meiotic pairing; instead, we find abundant evidence of gene conversion, which may limit the accumulation of deleterious mutations in the absence of meiosis. Gene families involved in resistance to oxidation, carbohydrate metabolism and defence against transposons are significantly expanded, which may explain why transposable elements cover only 3% of the assembled sequence. Furthermore, 8% of the genes are likely to be of non-metazoan origin and were probably acquired horizontally. This apparent convergence between bdelloids and prokaryotes sheds new light on the evolutionary significance of sex. [less ▲]

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See detailGenomic expression evaluation: introduction and perspectives
Ramery, Eve ULg; Bureau, Fabrice ULg; Guyot, Hugues ULg et al

Conference (2010, July)

In a way, disease could be considered as the result of gene expression deregulation. Knowing what genes are expressed in a particular cell or tissue and how they are regulated allow to better understand ... [more ▼]

In a way, disease could be considered as the result of gene expression deregulation. Knowing what genes are expressed in a particular cell or tissue and how they are regulated allow to better understand disease mechanisms. Transcriptomic is the study of the expression of the entire genome. This technical challenge has been rendered possible as different species’ genomes began to be sequenced. Several techniques have rendered efficient this process of measuring simultaneously the expression level of a large number of genes. To date, micro-array technology is probably the best known. However, with the development of more affordable techniques, sequencing/ resequencing could compete with microarrays in the future. All together, these techniques open new ways for early diagnosis and prognosis for the practioner ‘in the field’. [less ▲]

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See detailGenomic integration of bovine leukemia provirus and lack of viral RNA expression in the target cells of cattle with different responses to BLV infection.
Kettmann, Richard; Marbaix, Gérard; Cleuter, Yvette et al

in Leukemia Research (1980), 4

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See detailGenomic location of the bovine growth hormone secretagogue receptor (Ghsr) gene and investigation of genetic polymorphism
Colinet, Frédéric ULg; Vanderick, Sylvie ULg; Charloteaux, Benoît ULg et al

in Animal Biotechnology (2009), 20(1), 28-33

The growth hormone secretagogue receptor (GHSR) is involved in the regulation of energetic homeostasis and GH secretion. In this study, the bovine GHSR gene was mapped to BTA1 between BL26 and BMS4004 ... [more ▼]

The growth hormone secretagogue receptor (GHSR) is involved in the regulation of energetic homeostasis and GH secretion. In this study, the bovine GHSR gene was mapped to BTA1 between BL26 and BMS4004. Two different bovine GHSR CDS (GHSR1a and GHSR1b) were sequenced. Six polymorphisms (five SNPs and one 3-bp indel) were also identified, three of them leading to amino acid variations L24V, D194N, and Del R242. These variations are located in the extracellular N-terminal end, the exoloop 2, and the cytoloop 3 of the receptor, respectively. [less ▲]

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See detailGenomic screening and replication in one data set in family-based association testing
Lange, C.; Van Steen, Kristel ULg; McQueen, M. et al

in Conference Abstract Book (2005)

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See detailGenomic screening and replication using the same data set in family-based association testing
Van Steen, Kristel ULg; McQueen, M. B.; Herbert, A. et al

in Nature Genetics (2005), 37(7), 683-691

The Human Genome Project and its spin- offs are making it increasingly feasible to determine the genetic basis of complex traits using genome- wide association studies. The statistical challenge of ... [more ▼]

The Human Genome Project and its spin- offs are making it increasingly feasible to determine the genetic basis of complex traits using genome- wide association studies. The statistical challenge of analyzing such studies stems from the severe multiple-comparison problem resulting from the analysis of thousands of SNPs. Our methodology for genome- wide family- based association studies, using single SNPs or haplotypes, can identify associations that achieve genome- wide significance. In relation to developing guidelines for our screening tools, we determined lower bounds for the estimated power to detect the gene underlying the disease- susceptibility locus, which hold regardless of the linkage disequilibrium structure present in the data. We also assessed the power of our approach in the presence of multiple disease- susceptibility loci. Our screening tools accommodate genomic control and use the concept of haplotype- tagging SNPs. Our methods use the entire sample and do not require separate screening and validation samples to establish genome- wide significance, as population- based designs do. [less ▲]

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See detailGenomic screening in family-based association testing
Murphy, A.; McGueen, M. B.; Su, J. et al

in Genetic Epidemiology. Supplement (2005), 29

Due to the recent gains in the availability of single-nucleotide polymorphism data, genome-wide association testing has become feasible. It is hoped that this additional data may confirm the presence of ... [more ▼]

Due to the recent gains in the availability of single-nucleotide polymorphism data, genome-wide association testing has become feasible. It is hoped that this additional data may confirm the presence of disease susceptibility loci, and identify new genetic determinants of disease. However, the problem of multiple comparisons threatens to diminish any potential gains from this newly available data. To circumvent the multiple comparisons issue, we utilize a recently developed screening technique using family-based association testing. This screening methodology allows for the identification of the most promising single-nucleotide polymorphisms for testing without biasing the nominal significance level of our test statistic. We compare the results of our screening technique across univariate and multivariate family-based association tests. From our analyses, we observe that the screening technique, applied to different settings, is fairly consistent in identifying optimal markers for testing. One of the identified markers, TSC0047225, was significantly associated with both the ttth1 (p=0.004) and ttth1-ttth4 (p=0.004) phenotype(s). We find that both univariate- and multivariate-based screening techniques are powerful tools for detecting an association. [less ▲]

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