3912 results for "*geneti*"

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• WTCCC3_Anorexia_Nervosa

  As part of the Genetic Consortium for Anorexia Nervosa (GCAN) and Wellcome Trust CaseControl Consortium 3 (WTCCC3), we have amassed the largest anorexia nervosa (AN)sample in the world (~4,000). Following the WTCCC3 GWAS, we secured funding from theKlarman Family Foundation to extend the genetic analyses to variants on the exome chip(CoreExome array). This pre-lim relates to carrying out genotyping on the CoreExome arrayon up to a maximum of 580 new samples.

  Study EGAS00001000913

• Dissecting intratumor heterogeneity of nodal B cell lymphoma on the transcriptional, genetic, and drug response level

  Tumor heterogeneity encompasses both the malignant cells and their microenvironment. While heterogeneity between individual patients is well-known to affect the efficacy of anti-cancer, most personalized treatment approaches do not account for intratumor heterogeneity. We addressed this issue by studying the heterogeneity of lymph node-derived B cell non-Hodgkin lymphoma (B-NHL) by single cell RNA-sequencing (scRNA-seq) and transcriptome-informed flow cytometry. We identified transcriptionally distinct malignant subclones and compared their drug response and genomic profiles. Malignant subclones of the same patient responded strikingly different to anti-cancer drugs ex vivo, which recapitulated subclone-specific drug sensitivity during in vivo treatment. Tumor infiltrating T cells represented the majority of non-malignant cells, whose gene expression signatures were similar across all donors, whereas the frequencies of T cell subsets varied significantly between the donors. Our data provide new insights into the heterogeneity of B-NHL and highlight the relevance of intratumor heterogeneity for personalized cancer therapies.

  Study EGAS00001004335

• Genome_wide_association_study_of_vaccine_responses_in_infants_living_in_the_Developing_World__VaccGene___Phase_II_African_Cohorts

  Human genetic heterogeneity accounts for approximately 70% of the observed variability inresponse to common childhood vaccinations. Identifying the elements of this heterogeneitywill enable the development of vaccines which have improved clinical and cost effectivenessthrough rational adjuventation approaches, or by targeting particular at-risk or responsivesubgroups. The studies published to date have been limited in terms of the number of vaccinesubtypes analysed, diversity of the populations included, sample sizes and breadth of otherenvironmental and lifestyle variables which may explain some of the remainder of variation inthe response to each vaccine. Nevertheless, these studies have proposed that the geneswhich harbour the variants associated with vaccine responsiveness reside within regions ofthe genome associated with immune function such as the HLA locus and FOXP1and ITGAL.We are proposing one of the largest genome-wide association studies of vaccine responseever undertaken, which will provide unparalleled power to identify the genetic factorsassociated with the response to all of the most commonly used childhood vaccinesworldwide. For the first phase of the project (Prelim I0308) we genotyped ca. 1,400 childrenfrom the Entebbe Mother and Baby (EMaB) study, an ongoing birth cohort in southernUganda, using the Illumina HumanOmni2.5-8 chip. Analyses for response to vaccinationagainst diphtheria, tetanus, pertussis, Haemophilus influenzae, measles, hepatitis B and BCGare now underway. Working alongside other ongoing studies, we plan for the second phaseof the project to expand sample sizes to up to 7,000 individuals in total. This large cohort willinclude 1,500 South African infants, 500 Burkina Faso infants, 1,800 children from Ecuadorand up to 1,800 from a variety of countries (MAL-ED Consortium). The principal measuredphenotypes will be the serological responses at 6 or 12 months of age to the vaccinesadministered to all enrolled children as part of expanded programme of immunisation in allcountries. As for the primary Ugandan study the responses will be analysed as quantitativetraits using mixed model (GEMMA) analyses following imputation using a combined 1000Genome and African Genome Variation Project reference panel. The data will be analysed asone large discovery mega-analysis to maximise the power of finding the relevant associatedvariants. Interim GWAS analyses will be performed on each population to test for populationspecific signals. Other phenotypes that will be assessed in the new studies includequantitative response to BCG, rotavirus and pneumococcal vaccines (South Africa, Ecuadorand Uganda), clinical and immunological response to malaria vaccines (Burkina),immunological correlates of atopy (Ecuador and Uganda) and malaria infection (Burkina,Ecuador and Uganda) in addition to non-communicable disease traits such as blood pressurepage 1[A8] If applicable, provide text (abstract) which will accompany data for this study in the ENA/EGA.[A9] Does this project use samples?[A10] Please choose which types of sample you will be using[A12] Please state the anticipated date (month/year) samples will be available in-house (if known). If samples arealready in-house, type 'in-house' here. Please note that for sequencing, genotyping and microarrays this is essentialfor scheduling the work.[A13] Please state the anticipated project start date (month/year).[A14] Please state the project duration (months).[A15] Please read WTSI's Data Sharing Policy and Guidelines, then explain your data sharing plans for the project[A16] Are the data sharing plans of this project compliant with the Institute's Guidelines?[A17] Are there any conflicts of interest related to this proposal?(Uganda).We are requesting funds to genotype on the Illumina HumanOmni2.5-8 platform 2,000 Africaninfants recruited through ongoing maternal and child vaccine clinical trials (againstpneumococcus in Soweto, South Africa, and malaria in Banfora, Burkina Faso). The DNAfrom the Burkina cohort is at the University of Oxford and ready to be shipped, while the DNAfrom the South African cohort will be available by mid-2014. Appropriate consent for geneticanalyses has been acquired for the proposed study cohorts from both local ethics committeesand UK-based Committees.

  Study EGAS00001000918

• Therapeutic Resistance to PI3K-alpha Inhibitors

  We have studied the tumor genomic evolution in a patient with metastatic breast cancer bearing an activating PIK3CA mutation. The patient was treated with the PI3Kα inhibitor BYL719 and achieved a lasting clinical response on BYL719, but eventually progressed to treatment and died shortly thereafter. A rapid autopsy was performed and a total of 14 metastatic lesions were collected for further analysis. In order to identify possible genetic determinants of acquired resistance to PI3Kα inhibition, we took a three-step approach. First, we examined both the primary tumor (before BYL719 treatment) and the new lung metastasis by whole genome sequencing (DNA from the spleen was used as a normal control). Then, we analyzed the primary tumor, lung metastasis, and the peri-aortic lesion that remained stable (responding) at the time of progression to BYL719 therapy by whole exome sequencing. Finally, to confirm and expand our findings, we sequenced the primary tumor and all the metastatic lesions to >500-fold coverage using a custom targeted deep-sequencing assay, MSK-IMPACT. Using this 3-step approach, we have demonstrated that patient’s lesion underwent parallel genetic evolution at multiple metastatic sites with different PTEN genomic alterations leading to a convergent PTEN- null phenotype resistant to PI3Kα inhibition. In order to expand our observations, we analyzed paired samples (pre-treatment and at progression) from six additional patients enrolled in the BYL719 trial. Acquired bi-allelic loss of PTEN was found in one additional patient treated with BYL719 whereas in two patients PIK3CA mutations present in the primary tumor were no longer detected at the time of progression. To functionally characterize our findings, inducible PTEN knockdown in sensitive cells resulted in resistance to BYL719, while simultaneous PI3K-p110β blockade reverted this resistance phenotype, both in cell lines and in PTEN-null xenografts derived from our patient. We conclude that parallel genetic evolution of separate sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI3Kα inhibition.

  Study EGAS00001000991

• Whole-exome sequencing of extranodal NK/T cell lymphoma

  Extranodal NK/T cell lymphoma (ENKTCL) is an aggressive Epstein-Barr virus-associated T/NK neoplasm that predominantly affects Asians. To explore the causative somatic events, we conducted a comprehensive genetic analysis of 19 ENKTCL patients including whole-exome sequencing (N = 16). Commonly deregulated gene pathways in ENKTCL included epigenetic modifiers followed by human leukocyte antigen (HLA) and related genes and JAK-STAT pathway.

  Study EGAS00001004357

• Ischemic stroke in a Swedish case-control study.

  Background. Genetic risk scores (GRS), summing up the total effect of several single nucleotide polymorphisms (SNPs) in genes associated with either coronary risk or cardiovascular risk factors, have been tested for association with ischemic stroke with conflicting results. Recently an association was found between a GRS, based on 29 SNPs discovered by genome-wide association studies (GWAS) and hypertension. The aim of our study was to investigate the possible association of the same GRS with ischemic stroke on top of other “traditional risk factors”, also testing its potential improvement in indices of discrimination and reclassification, in a Swedish case-control study. Methods and results. Twenty-nine SNPs were genotyped in 3,677 stroke cases and 2,415 controls included in the Lund Stroke Register (LSR), the Malmö Diet and Cancer (MDC) study and the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The analysis was conducted in the entire material, and separately for the three samples. After adjustment for hypertension, diabetes mellitus and smoking habits, the GRS was associated with ischemic stroke in the entire material [OR (95% CI) 1.086 (1.029-1.147) per SD increase in the GRS p=0.003] with similar trends in all three samples; LSR [1.050 (0.967-1.140)]; p=0.25], MDC [1.168 (1.060-1.288); p=0.002] and SAHLSIS [1.124 (0.997-1.267); P=0.055]. Measures of discrimination and reclassification improved marginally using the GRS. Conclusions. A blood pressure GRS is independently associated with ischemic stroke risk in three Swedish case-control studies, however, the effect size is low and adds marginally to prediction of stroke on top of traditional risk factors including hypertension.

  Study EGAS00001000936

• Whole genome sequencing of 25 South African individuals with myasthenia gravis

  This study investigated the genetic basis of an ophthalmoplegic subphenotype of MG (OP-MG) which occurs in a proportion of myasthenics with juvenile symptom onset and African genetic ancestry. This OP-MG subphenotype is characterised by treatment resistant weakness of the extraocular muscles (EOMs) and the pathogenetic mechanism(s) underlying its development is unknown. The aim of this study was to use a hypothesis-generating genome-wide case-control analysis to identify candidate OP-MG susceptibility genes and pathways. Whole genome sequencing (WGS) was performed on 25 AChR-antibody positive myasthenic individuals of African genetic ancestry sampled from the phenotypic extremes: 15 with OP-MG (cases) and 10 individuals with control MG (EOM treatment-responsive).

  Study EGAS00001003462

• Whole-genome sequencing of rare disease patients in a national healthcare system

  Most patients with rare diseases do not receive a molecular diagnosis and the aetiologicalvariants and mediating genes for more than half such disorders remain to be discovered. Weimplemented whole-genome sequencing (WGS) in a national healthcare system to streamlinediagnosis and to discover unknown aetiological variants, in the coding and non-coding regionsof the genome. In a pilot study for the 100,000 Genomes Project, we generated WGS data for13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to1,138 of the 7,065 patients with detailed phenotypic data. We identified 95 Mendelianassociations between genes and rare diseases, of which 11 have been discovered since 2015and at least 79 are confirmed aetiological. Using WGS of UK Biobank1, we showed that rarealleles can explain the presence of some individuals in the tails of a quantitative red blood cell(RBC) trait. Finally, we reported 4 novel non-coding variants which cause disease through thedisruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates asynergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

  Study EGAS00001004364

• Genome-wide prediction of human embryos

  BACKGROUND: Preimplantation genetic diagnosis (PGD) enables profiling of embryos for genetic disorders prior to implantation. The majority of PGD testing is restricted in the scope of variants assayed or by the availability of extended family members. While recent advances in single cell sequencing show promise, they remain limited by bias in DNA amplification and the rapid turnaround time (<36 h) required for fresh embryo transfer. Here, we describe and validate a method for inferring the inherited whole genome sequence of an embryo for preimplantation genetic diagnosis (PGD). METHODS: We combine haplotype-resolved, parental genome sequencing with rapid embryo genotyping to predict the whole genome sequence of a day-5 human embryo in a couple at risk of transmitting alpha-thalassemia. RESULTS: Inheritance was predicted at approximately 3 million paternally and/or maternally heterozygous sites with greater than 99% accuracy. Furthermore, we successfully phase and predict the transmission of an HBA1/HBA2 deletion from each parent. CONCLUSIONS: Our results suggest that preimplantation whole genome prediction may facilitate the comprehensive diagnosis of diseases with a known genetic basis in embryos.

  Study EGAS00001001020

• Genetic_profiling_of_mucosal_melanoma

  Primary mucosal melanomas (MMs) arise from melanocytes located in mucosal membranes lining the respiratory, gastrointestinal and urogenital tracts. MMs frequently present late and have a poor prognosis; the 5-year survival rate is only 14%. MM makes up only ~1.4% of all melanomas and it is this rarity that makes knowledge of the genetic changes that contribute to its pathogenesis limited to a small number of exome/genome studies and other targeted studies. Thus to investigate the somatic alterations and mutation spectra in MM genomes, we have extracted genomic DNA from formalin-fixed, paraffin-embedded (FFPE) human MMs, and subjected them to whole exome sequencing. Given the propensity of MM to metastasize, we will also be sequencing metastatic MM lesions; primary and metastatic lesions from the same individual represent an excellent opportunity to identify potential drivers of metastasis in MM. Finally we will sequence ‘normal’ DNA from the same individual, where possible, to exclude germline variations.

  Study EGAS00001001115