ORCID Profile
0000-0002-7144-4579
Current Organisations
Cambridge University Hospitals
,
Gonville and Caius College, University of Cambridge
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Publisher: Cold Spring Harbor Laboratory
Date: 13-07-2017
DOI: 10.1101/143933
Abstract: We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain - resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system. We report a detailed genetic and genomic map of multiple sclerosis, and describe the role of putatively affected genes in the peripheral immune system and brain resident microglia.
Publisher: Springer Science and Business Media LLC
Date: 17-07-2019
DOI: 10.1038/S41598-019-46649-Z
Abstract: Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2008
DOI: 10.1038/NG.145
Publisher: Springer Science and Business Media LLC
Date: 05-01-2015
DOI: 10.1038/NG.3176
Publisher: Springer Science and Business Media LLC
Date: 31-10-2012
DOI: 10.1038/NATURE11582
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.JHIN.2018.05.001
Abstract: All courses of fidaxomicin use in the study hospital were reviewed. It was used for first recurrence (six times), second recurrence (eight times) and one case of third recurrence. One patients received fidaxomicin as first-line treatment. Eight patients initially responded to therapy of these, three patients were asymptomatic at 90 days, three patients remained asymptomatic at 30 days, and two patients had recurrences five and nine days after stopping therapy. Four patients failed to respond of these, two patients required faecal transplantation and one patient required a colectomy. Two patients deteriorated and two patients died. Fidaxomicin was well tolerated. These findings suggest that the utility of fidaxomicin at this stage of infection is unclear.
Publisher: Springer Science and Business Media LLC
Date: 04-2010
DOI: 10.1038/NATURE08979
Publisher: Springer Science and Business Media LLC
Date: 28-10-2012
DOI: 10.1038/NG.2435
Publisher: Springer Science and Business Media LLC
Date: 20-07-2015
DOI: 10.1038/NG.3359
Publisher: Elsevier BV
Date: 2016
Publisher: Oxford University Press (OUP)
Date: 11-04-2014
DOI: 10.1093/HMG/DDU174
Publisher: Springer Science and Business Media LLC
Date: 21-06-2018
DOI: 10.1038/S41467-018-04365-8
Abstract: GWAS have identified risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis -eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger s le sizes will be required to demonstrate the causality of in idual genes using this approach.
Location: No location found
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Dunecan Massey.