9 results found
Speed D, Hoggart C, Petrovski S, et al., 2014, Genome-wide association study and biological pathway analysis of epilepsy prognosis in a prospective cohort of newly treated epilepsy, Human Molecular Genetics
Munhoz RP, Teive HA, Eleftherohorinou H, et al., 2013, Demographic and motor features associated with the occurrence of neuropsychiatric and sleep complications of Parkinson's disease, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 84, Pages: 883-887, ISSN: 0022-3050
El-Sayed Moustafa JS, Eleftherohorinou H, de Smith AJ, et al., 2012, Novel association approach for variable number tandem repeats (VNTRs) identifies DOCK5 as a susceptibility gene for severe obesity, Hum Mol Genet, Vol: 21, Pages: 3727-3738, ISSN: 1460-2083
Variable number tandem repeats (VNTRs) constitute a relatively under-examined class of genomic variants in the context of complex disease because of their sequence complexity and the challenges in assaying them. Recent large-scale genome-wide copy number variant mapping and association efforts have highlighted the need for improved methodology for association studies using these complex polymorphisms. Here we describe the in-depth investigation of a complex region on chromosome 8p21.2 encompassing the dedicator of cytokinesis 5 (DOCK5) gene. The region includes two VNTRs of complex sequence composition which flank a common 3975 bp deletion, all three of which were genotyped by polymerase chain reaction and fragment analysis in a total of 2744 subjects. We have developed a novel VNTR association method named VNTRtest, suitable for association analysis of multi-allelic loci with binary and quantitative outcomes, and have used this approach to show significant association of the DOCK5 VNTRs with childhood and adult severe obesity (P(empirical)= 8.9 x 10(-8) and P= 3.1 x 10(-3), respectively) which we estimate explains ~0.8% of the phenotypic variance. We also identified an independent association between the 3975 base pair (bp) deletion and obesity, explaining a further 0.46% of the variance (P(combined)= 1.6 x 10(-3)). Evidence for association between DOCK5 transcript levels and the 3975 bp deletion (P= 0.027) and both VNTRs (P(empirical)= 0.015) was also identified in adipose tissue from a Swedish family sample, providing support for a functional effect of the DOCK5 deletion and VNTRs. These findings highlight the potential role of DOCK5 in human obesity and illustrate a novel approach for analysis of the contribution of VNTRs to disease susceptibility through association studies.
Pathan N, Franklin JL, Eleftherohorinou H, et al., 2011, Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase, CRITICAL CARE MEDICINE, Vol: 39, Pages: 1692-1711, ISSN: 0090-3493
Eleftherohorinou H, Hoggart CJ, Wright VJ, et al., 2011, Pathway-driven gene stability selection of two rheumatoid arthritis GWAS identifies and validates new susceptibility genes in receptor mediated signalling pathways, Human Molecular Genetics, Vol: 20, Pages: 3494-3506
Shimizu C, Jain S, Davila S, et al., 2011, Transforming Growth Factor-beta Signaling Pathway in Patients With Kawasaki Disease, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 4, Pages: 16-U99, ISSN: 1942-325X
Eleftherohorinou H, Andersson-Assarsson JC, Walters RG, et al., 2011, famCNV: copy number variant association for quantitative traits in families, Bioinformatics, Vol: 27, Pages: 1873-1875, ISSN: 1367-4811
A program package to enable genome-wide association of copy number variants (CNVs) with quantitative phenotypes in families of arbitrary size and complexity. Intensity signals that act as proxies for the number of copies are modeled in a variance component framework and association with traits is assessed through formal likelihood testing. AVAILABILITY AND IMPLEMENTATION: The Java package is made available at www.imperial.ac.uk/medicine/people/m.falchi/. CONTACT: firstname.lastname@example.org.
Eleftherohorinou H, Wright V, Hoggart C, et al., 2009, Analysis of GWAS provides new insights into genetic susceptibility to 3 inflammatory diseases, PLoS One, Vol: 4, Pages: 1-11, ISSN: 1932-6203
Although the introduction of genome-wide association studies (GWAS) have greatly increased the number of genes associated with common diseases, only a small proportion of the predicted genetic contribution has so far been elucidated. Studying the cumulative variation of polymorphisms in multiple genes acting in functional pathways may provide a complementary approach to the more common single SNP association approach in understanding genetic determinants of common disease. We developed a novel pathway-based method to assess the combined contribution of multiple genetic variants acting within canonical biological pathways and applied it to data from 14,000 UK individuals with 7 common diseases. We tested inflammatory pathways for association with Crohn's disease (CD), rheumatoid arthritis (RA) and type 1 diabetes (T1D) with 4 non-inflammatory diseases as controls. Using a variable selection algorithm, we identified variants responsible for the pathway association and evaluated their use for disease prediction using a 10 fold cross-validation framework in order to calculate out-of-sample area under the Receiver Operating Curve (AUC). The generalisability of these predictive models was tested on an independent birth cohort from Northern Finland. Multiple canonical inflammatory pathways showed highly significant associations (p 10−3–10−20) with CD, T1D and RA. Variable selection identified on average a set of 205 SNPs (149 genes) for T1D, 350 SNPs (189 genes) for RA and 493 SNPs (277 genes) for CD. The pattern of polymorphisms at these SNPS were found to be highly predictive of T1D (91% AUC) and RA (85% AUC), and weakly predictive of CD (60% AUC). The predictive ability of the T1D model (without any parameter refitting) had good predictive ability (79% AUC) in the Finnish cohort. Our analysis suggests that genetic contribution to common inflammatory diseases operates through multiple genes interacting in functional pathways.
Trepel M, Stoneham CA, Eleftherohorinou H, et al., 2009, A heterotypic bystander effect for tumor cell killing after adeno-associated virus/phage-mediated, vascular-targeted suicide gene transfer, MOLECULAR CANCER THERAPEUTICS, Vol: 8, Pages: 2383-2391, ISSN: 1535-7163
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