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See detailA family-based association test to detect gene-gene interactions in the presence of linkage
De Lobel, Lizzy; Thijs, L; Kouznetsova, T et al

in European Journal of Human Genetics (2012)

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See detailClinical utility gene card for: Biotinidase deficiency
Küry, S.; RAMAEKERS, Vincent ULg; Bézieau, S. et al

in European Journal of Human Genetics (2012), 20(5), 592

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See detailModel-Based Multifactor Dimensionality Reduction to detect epistasis for quantitative traits in the presence of error-free and noisy data.
Mahachie John, Jestinah ULg; Van Lishout, François ULg; Van Steen, Kristel ULg

in European Journal of Human Genetics (2011), 19

Detecting gene-gene interactions or epistasis in studies of human complex diseases is a big challenge in the area of epidemiology. To address this problem, several methods have been developed, mainly in ... [more ▼]

Detecting gene-gene interactions or epistasis in studies of human complex diseases is a big challenge in the area of epidemiology. To address this problem, several methods have been developed, mainly in the context of data dimensionality reduction. One of these methods, Model-Based Multifactor Dimensionality Reduction, has so far mainly been applied to case-control studies. In this study, we evaluate the power of Model-Based Multifactor Dimensionality Reduction for quantitative traits to detect gene-gene interactions (epistasis) in the presence of error-free and noisy data. Considered sources of error are genotyping errors, missing genotypes, phenotypic mixtures and genetic heterogeneity. Our simulation study encompasses a variety of settings with varying minor allele frequencies and genetic variance for different epistasis models. On each simulated data, we have performed Model-Based Multifactor Dimensionality Reduction in two ways: with and without adjustment for main effects of (known) functional SNPs. In line with binary trait counterparts, our simulations show that the power is lowest in the presence of phenotypic mixtures or genetic heterogeneity compared to scenarios with missing genotypes or genotyping errors. In addition, empirical power estimates reduce even further with main effects corrections, but at the same time, false-positive percentages are reduced as well. In conclusion, phenotypic mixtures and genetic heterogeneity remain challenging for epistasis detection, and careful thought must be given to the way important lower-order effects are accounted for in the analysis.European Journal of Human Genetics advance online publication, 16 March 2011; doi:10.1038/ejhg.2011.17. [less ▲]

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See detailA screening methodology based on Random Forests to improve the detection of gene-gene interactions
De Lobel, L.; Geurts, Pierre ULg; Baele, G. et al

in European Journal of Human Genetics (2010), 18(1127), 1132

The search for susceptibility loci in gene-gene interactions imposes a methodological and computational challenge for statisticians because of the large dimensionality inherent to the modelling of gene ... [more ▼]

The search for susceptibility loci in gene-gene interactions imposes a methodological and computational challenge for statisticians because of the large dimensionality inherent to the modelling of gene-gene interactions or epistasis. In an era in which genome-wide scans have become relatively common, new powerful methods are required to handle the huge amount of feasible gene-gene interactions and to weed out false positives and negatives from these results. One solution to the dimensionality problem is to reduce data by preliminary screening of markers to select the best candidates for further analysis. Ideally, this screening step is statistically independent of the testing phase. Initially developed for small numbers of markers, the Multifactor Dimensionality Reduction (MDR) method is a nonparametric, model-free data reduction technique to associate sets of markers with optimal predictive properties to disease. In this study, we examine the power of MDR in larger data sets and compare it with other approaches that are able to identify gene-gene interactions. Under various interaction models (purely and not purely epistatic), we use a Random Forest (RF)-based prescreening method, before executing MDR, to improve its performance. We find that the power of MDR increases when noisy SNPs are first removed, by creating a collection of candidate markers with RFs. We validate our technique by extensive simulation studies and by application to asthma data from the European Committee of Respiratory Health Study II.European Journal of Human Genetics advance online publication, 12 May 2010; doi:10.1038/ejhg.2010.48. [less ▲]

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See detailBCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects.
Hilton, Emma; Johnston, Jennifer; Whalen, Sandra et al

in European Journal of Human Genetics (2009), 17(10), 1325-35

Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental ... [more ▼]

Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations in BCOR, we sequenced the BCOR gene in patients with (1) OFCD syndrome, (2) putative X-linked ('Lenz') microphthalmia syndrome, (3) isolated ocular defects and (4) laterality phenotypes. We present a new cohort of females with OFCD syndrome and null mutations in BCOR, supporting the hypothesis that BCOR is the sole molecular cause of this syndrome. We identify for the first time mosaic BCOR mutations in two females with OFCD syndrome and one apparently asymptomatic female. We present a female diagnosed with isolated ocular defects and identify minor features of OFCD syndrome, suggesting that OFCD syndrome may be mild and underdiagnosed. We have sequenced a cohort of males diagnosed with putative X-linked microphthalmia and found a mutation, p.P85L, in a single case, suggesting that BCOR mutations are not a major cause of X-linked microphthalmia in males. The absence of BCOR mutations in a panel of patients with non-specific laterality defects suggests that mutations in BCOR are not a major cause of isolated heart and laterality defects. Phenotypic analysis of OFCD and Lenz microphthalmia syndromes shows that in addition to the standard diagnostic criteria of congenital cataract, microphthalmia and radiculomegaly, patients should be examined for skeletal defects, particularly radioulnar synostosis, and cardiac/laterality defects. [less ▲]

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See detailGENESTAT: an information portal for design and analysis of genetic association studies
Ripatti, Samuli; Becker, Tim; Bickeboller, Heike et al

in European Journal of Human Genetics (2009), 17(4), 533-6

We present the rationale, the background and the structure for version 2.0 of the GENESTAT information portal (www.genestat.org) for statistical genetics. The fast methodological advances, coupled with a ... [more ▼]

We present the rationale, the background and the structure for version 2.0 of the GENESTAT information portal (www.genestat.org) for statistical genetics. The fast methodological advances, coupled with a range of standalone software, makes it difficult for expert as well as non-expert users to orientate when designing and analysing their genetic studies. The ultimate ambition of GENESTAT is to guide on statistical methodology related to the broad spectrum of research in genetic epidemiology. GENESTAT 2.0 focuses on genetic association studies. Each entry provides a summary of a topic and gives links to key papers, websites and software. The flexibility of the internet is utilised for cross-referencing and for open editing. This paper gives an overview of GENESTAT and gives short introductions to the current main topics in GENESTAT, with additional entries on the website. Methods and software developers are invited to contribute to the portal, which is powered by a Wikipedia-type engine and allows easy additions and editing. [less ▲]

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See detailInvestigation of the fine structure of European populations with applications to disease association studies
heath, sc; gut, ivo; brennan, p et al

in European Journal of Human Genetics (2008), 16

An investigation into fine-scale European population structure was carried out using high-density genetic variation on nearly 6000 individuals originating from across Europe. The individuals were ... [more ▼]

An investigation into fine-scale European population structure was carried out using high-density genetic variation on nearly 6000 individuals originating from across Europe. The individuals were collected as control samples and were genotyped with more than 300 000 SNPs in genome-wide association studies using the Illumina Infinium platform. A major East-West gradient from Russian (Moscow) samples to Spanish samples was identified as the first principal component (PC) of the genetic diversity. The second PC identified a North-South gradient from Norway and Sweden to Romania and Spain. Variation of frequencies at markers in three separate genomic regions, surrounding LCT, HLA and HERC2, were strongly associated with this gradient. The next 18 PCs also accounted for a significant proportion of genetic diversity observed in the sample. We present a method to predict the ethnic origin of samples by comparing the sample genotypes with those from a reference set of samples of known origin. These predictions can be performed using just summary information on the known samples, and individual genotype data are not required. We discuss issues raised by these data and analyses for association studies including the matching of case-only cohorts to appropriate pre-collected control samples for genome-wide association studies. [less ▲]

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See detailVALAPODYN: Validated Predictive Dynamic Model of Complex Intracellular Pathways Related to Cell Death and Survival
Depaulis, Antoine; Vafiadaki, Elizabeth; Jackers, Pascale ULg et al

in European Journal of Human Genetics (2007), 15(Suppl. 1),

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See detailMajor Decrease in the Incidence of Trisomy 21 at Birth in South Belgium: Mass Impact of Triple Test?
Verloes, Alain ULg; Gillerot, Y.; Van Maldergem, Lionel ULg et al

in European Journal of Human Genetics (2001), 9(1), 1-4

In South Belgium (Wallonia), the 'triple test' was introduced in 1990-1991, and is nowadays a widely accepted screening method for assessment of trisomy 21 risk in pregnancy. The 'triple test' is not ... [more ▼]

In South Belgium (Wallonia), the 'triple test' was introduced in 1990-1991, and is nowadays a widely accepted screening method for assessment of trisomy 21 risk in pregnancy. The 'triple test' is not regulated and can be freely performed by any biomedical lab, making epidemiological data unavailable. By contrast, cytogenetic investigations are limited to a few genetic centres, and accurate statistics can be easily built from their files. During the period 1984-1989, a total of 244 trisomy 21 (1/876 pregnancies) were diagnosed in the Genetic Centres of Liege and Loverval, 42 (17%) of them prenatally. During the period 1993-1998, 294 trisomy 21 (1/704 pregnancies) were observed, 165 (56%) of which prenatally, and more than 90% of affected pregnancies were terminated. Even after correction for late foetal loss of trisomic foetuses, the difference is highly significant, and corresponds to a theoretical shift in the incidence of trisomy 21 at birth from 1/794 to 1/1606. As no remarkable progress occurred in other non-invasive prenatal screening procedures or general health care policies in Belgium, the most reasonable explanation is the use on a large scale of triple test by pregnant women, and the election of termination for most affected pregnancies. [less ▲]

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