ORCID Profile
0000-0002-1901-8265
Current Organisations
University of Manchester
,
Harvard Medical School
,
Broad Institute
,
Brigham and Women's Hospital
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Publisher: Springer Science and Business Media LLC
Date: 14-03-2016
DOI: 10.1038/NG.3528
Publisher: Springer Science and Business Media LLC
Date: 08-11-2009
DOI: 10.1038/NG.479
Publisher: Public Library of Science (PLoS)
Date: 26-06-2009
Publisher: Public Library of Science (PLoS)
Date: 10-03-2011
Publisher: Public Library of Science (PLoS)
Date: 07-08-2014
Publisher: Oxford University Press (OUP)
Date: 10-06-2011
DOI: 10.1093/HMG/DDR270
Publisher: Elsevier BV
Date: 08-2016
Publisher: Elsevier BV
Date: 2013
Publisher: BMJ
Date: 20-12-2016
DOI: 10.1136/ANNRHEUMDIS-2016-210025
Abstract: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.
Publisher: Public Library of Science (PLoS)
Date: 09-09-2010
Publisher: Oxford University Press (OUP)
Date: 28-07-2014
DOI: 10.1093/HMG/DDU387
Publisher: Public Library of Science (PLoS)
Date: 13-01-2011
Publisher: Elsevier BV
Date: 09-2012
Publisher: BMJ
Date: 28-04-2018
Publisher: Springer Science and Business Media LLC
Date: 12-08-2012
DOI: 10.1038/NG.2385
Publisher: Public Library of Science (PLoS)
Date: 22-12-2015
Publisher: Springer Science and Business Media LLC
Date: 16-05-2016
DOI: 10.1038/NG.3572
Publisher: Springer Science and Business Media LLC
Date: 22-06-2014
DOI: 10.1038/NG.3014
Publisher: Elsevier BV
Date: 09-2016
Publisher: Springer Science and Business Media LLC
Date: 27-06-2010
DOI: 10.1038/NG.609
Publisher: Elsevier BV
Date: 09-2016
Publisher: American Society for Clinical Investigation
Date: 18-06-2020
Publisher: Springer Science and Business Media LLC
Date: 29-05-2017
DOI: 10.1038/NG.3875
Publisher: Cold Spring Harbor Laboratory
Date: 20-03-2023
DOI: 10.1101/2023.03.14.23287257
Abstract: The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation, and cancer. While coding variation in HLA genes has been extensively documented, regulatory genetic variation modulating HLA expression levels has not been comprehensively investigated. Here, we mapped expression quantitative trait loci (eQTLs) for classical HLA genes across 1,073 in iduals and 1,131,414 single cells from three tissues, using personalized reference genomes to mitigate technical confounding. We identified cell-type-specific cis- eQTLs for every classical HLA gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type. HLA-DQ genes exhibit particularly cell-state-dependent effects within myeloid, B, and T cells. Dynamic HLA regulation may underlie important interin idual variability in immune responses.
Publisher: Springer Science and Business Media LLC
Date: 14-06-2009
DOI: 10.1038/NG.401
Publisher: Oxford University Press (OUP)
Date: 18-08-2015
DOI: 10.1093/IJE/DYV136
Publisher: Cold Spring Harbor Laboratory
Date: 06-11-2015
DOI: 10.1101/030783
Abstract: Shared genetic architecture between phenotypes may be driven by a common genetic basis (pleiotropy) or a subset of genetically similar in iduals (heterogeneity). We developed BUHMBOX, a well-powered statistical method to distinguish pleiotropy from heterogeneity using genotype data. We observed a shared genetic basis between 11 of 17 tested autoimmune diseases and type I diabetes (T1D, p 12) and 11 of 17 tested autoimmune diseases and rheumatoid arthritis (RA, p -7). This sharing could not be explained by heterogeneity (corrected pBUHMBOX .2 using 6,670 T1D cases and 7,279 RA cases), suggesting that shared genetic features in autoimmunity are due to pleiotropy. We observed a shared genetic basis between seronegative and seropostive RA (p -22), explained by heterogeneity (pBUHMBOX=0.008 in 2,406 seronegative RA cases). Consistent with previous observations, we observed genetic sharing between major depressive disorder (MDD) and schizophrenia (p 9). This sharing is not explained by heterogeneity (pBUHMBOX=0.28 in 9,238 MDD cases).
Publisher: Springer Science and Business Media LLC
Date: 25-12-2013
DOI: 10.1038/NATURE12873
Publisher: American Association for the Advancement of Science (AAAS)
Date: 10-05-2017
DOI: 10.1126/SCITRANSLMED.AAI8708
Abstract: Numerous associations were discovered between human leukocyte antigen (HLA) variation and a comprehensive set of phenotypes derived from electronic health records.
Publisher: Springer Science and Business Media LLC
Date: 08-10-2018
DOI: 10.1038/S42003-018-0155-Y
Abstract: Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree ( n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected in iduals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
Publisher: Springer Science and Business Media LLC
Date: 06-05-2019
Publisher: Springer Science and Business Media LLC
Date: 21-04-2023
Publisher: Springer Science and Business Media LLC
Date: 11-07-2018
Publisher: Proceedings of the National Academy of Sciences
Date: 23-11-2015
Abstract: To determine whether genetic variation within the MHC locus influences the risk of developing systemic juvenile idiopathic arthritis (sJIA), we examined a dense set of MHC region single nucleotide polymorphisms, classic HLA alleles, and the in idual amino acids of HLA molecules in nine independent sJIA case-control populations. Association testing revealed that genetic variants within the MHC class II gene cluster significantly influenced sJIA risk in every study population. The strongest risk factor for sJIA was HLA-DRB1*11 , which conferred at least a two-fold increase in disease risk in each population studied. These data implicate the interaction of antigen presenting cells with T cells in the pathogenesis of sJIA.
Publisher: BMJ
Date: 11-08-2017
DOI: 10.1136/ANNRHEUMDIS-2017-211300
Abstract: The pathogenetic mechanisms by which HLA-DRB1 alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 alleles are known to share a common motif, the ‘shared susceptibility epitope (SE)’. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine. HLA-DRB1 His/Phe13β stratifies with ACPA-positive RA, while His13βSer polymorphisms stratify with ACPA-negative RA and RA protection. Indigenous North American (INA) populations have high risk of early-onset ACPA-positive RA, whereby HLA-DRB1*04:04 and HLA-DRB1*14:02 are implicated as risk factors for RA in INA. However, HLA-DRB1*14:02 has a His13βSer polymorphism. Therefore, we aimed to verify this association and determine its molecular mechanism. HLA genotype was compared in 344 INA patients with RA and 352 controls. Structures of HLA-DRB1*1402-class II loaded with vimentin-64Arg 59-71 , vimentin-64Cit 59-71 and fibrinogen β−74Cit 69-81 were solved using X-ray crystallography. Vimentin-64Cit 59-71 -specific and vimentin 59-71 -specific CD4+ T cells were characterised by flow cytometry using peptide-histocompatibility leukocyte antigen (pHLA) tetramers. After sorting of antigen-specific T cells, TCRα and β-chains were analysed using multiplex, nested PCR and sequencing. ACPA + RA in INA was independently associated with HLA-DRB1*14:02 . Consequent to the His13βSer polymorphism and altered P4 pocket of HLA-DRB1*14:02, both citrulline and arginine were accommodated in opposite orientations. Oligoclonal autoreactive CD4+ effector T cells reactive with both citrulline and arginine forms of vimentin 59-71 were observed in patients with HLA-DRB1*14:02 + RA and at-risk ACPA - first-degree relatives. HLA-DRB1*14:02-vimentin 59-71 -specific and HLA-DRB1*14:02-vimentin-64Cit 59-71 -specific CD4+ memory T cells were phenotypically distinct populations. HLA-DRB1*14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA.
Publisher: Springer Science and Business Media LLC
Date: 10-11-2013
DOI: 10.1038/NG.3143
Publisher: Springer Science and Business Media LLC
Date: 31-10-2012
DOI: 10.1038/NATURE11582
Publisher: Springer Science and Business Media LLC
Date: 21-11-2010
DOI: 10.1038/NG.717
Publisher: Springer Science and Business Media LLC
Date: 09-02-2014
DOI: 10.1038/NG.2897
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
Publisher: Springer Science and Business Media LLC
Date: 11-08-2202
DOI: 10.1038/NG.2711
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: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Soumya Raychaudhuri.