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  1. Article ; Online: Accurate imputation of human leukocyte antigens with CookHLA

    Seungho Cook / Wanson Choi / Hyunjoon Lim / Yang Luo / Kunhee Kim / Xiaoming Jia / Soumya Raychaudhuri / Buhm Han

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 11

    Abstract: Human leukocyte antigen (HLA) genes influence many immune phenotypes, however methods to impute HLA type have been limited in accuracy. Here, the authors present an HLA imputation method, CookHLA, which uses locally embedded prediction markers to ... ...

    Abstract Human leukocyte antigen (HLA) genes influence many immune phenotypes, however methods to impute HLA type have been limited in accuracy. Here, the authors present an HLA imputation method, CookHLA, which uses locally embedded prediction markers to adaptively impute HLA genes across a range of scenarios.
    Keywords Science ; Q
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Efficient and precise single-cell reference atlas mapping with Symphony

    Joyce B. Kang / Aparna Nathan / Kathryn Weinand / Fan Zhang / Nghia Millard / Laurie Rumker / D. Branch Moody / Ilya Korsunsky / Soumya Raychaudhuri

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 21

    Abstract: The number of single-cell RNA-seq datasets generated is increasing rapidly, making methods that map cell types to well-curated references increasingly important. Here, the authors propose an accurate method for mapping single cells onto a reference atlas ...

    Abstract The number of single-cell RNA-seq datasets generated is increasing rapidly, making methods that map cell types to well-curated references increasingly important. Here, the authors propose an accurate method for mapping single cells onto a reference atlas in seconds.
    Keywords Science ; Q
    Language English
    Publishing date 2021-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: High-dimensional phenotyping to define the genetic basis of cellular morphology

    Matthew Tegtmeyer / Jatin Arora / Samira Asgari / Beth A. Cimini / Ajay Nadig / Emily Peirent / Dhara Liyanage / Gregory P. Way / Erin Weisbart / Aparna Nathan / Tiffany Amariuta / Kevin Eggan / Marzieh Haghighi / Steven A. McCarroll / Luke O’Connor / Anne E. Carpenter / Shantanu Singh / Ralda Nehme / Soumya Raychaudhuri

    Nature Communications, Vol 15, Iss 1, Pp 1-

    2024  Volume 12

    Abstract: Abstract The morphology of cells is dynamic and mediated by genetic and environmental factors. Characterizing how genetic variation impacts cell morphology can provide an important link between disease association and cellular function. Here, we combine ... ...

    Abstract Abstract The morphology of cells is dynamic and mediated by genetic and environmental factors. Characterizing how genetic variation impacts cell morphology can provide an important link between disease association and cellular function. Here, we combine genomic sequencing and high-content imaging approaches on iPSCs from 297 unique donors to investigate the relationship between genetic variants and cellular morphology to map what we term cell morphological quantitative trait loci (cmQTLs). We identify novel associations between rare protein altering variants in WASF2, TSPAN15, and PRLR with several morphological traits related to cell shape, nucleic granularity, and mitochondrial distribution. Knockdown of these genes by CRISPRi confirms their role in cell morphology. Analysis of common variants yields one significant association and nominate over 300 variants with suggestive evidence (P < 10−6) of association with one or more morphology traits. We then use these data to make predictions about sample size requirements for increasing discovery in cellular genetic studies. We conclude that, similar to molecular phenotypes, morphological profiling can yield insight about the function of genes and variants.
    Keywords Science ; Q
    Subject code 500
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Population-specific causal disease effect sizes in functionally important regions impacted by selection

    Huwenbo Shi / Steven Gazal / Masahiro Kanai / Evan M. Koch / Armin P. Schoech / Katherine M. Siewert / Samuel S. Kim / Yang Luo / Tiffany Amariuta / Hailiang Huang / Yukinori Okada / Soumya Raychaudhuri / Shamil R. Sunyaev / Alkes L. Price

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 15

    Abstract: Trans-ethnic genetic correlation is significantly less than 1 for many diseases. Here, the authors stratify this correlation by genomic annotations, finding that loci whose causal disease effect sizes differ between ethnicities are likely impacted by ... ...

    Abstract Trans-ethnic genetic correlation is significantly less than 1 for many diseases. Here, the authors stratify this correlation by genomic annotations, finding that loci whose causal disease effect sizes differ between ethnicities are likely impacted by selection, particularly positive selection.
    Keywords Science ; Q
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: A sex-specific evolutionary interaction between ADCY9 and CETP

    Isabel Gamache / Marc-André Legault / Jean-Christophe Grenier / Rocio Sanchez / Eric Rhéaume / Samira Asgari / Amina Barhdadi / Yassamin Feroz Zada / Holly Trochet / Yang Luo / Leonid Lecca / Megan Murray / Soumya Raychaudhuri / Jean-Claude Tardif / Marie-Pierre Dubé / Julie Hussin

    eLife, Vol

    2021  Volume 10

    Abstract: Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction ...

    Abstract Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of positive selection in several human populations. Furthermore, we identified a variant in CETP, rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population. The signal is mainly seen in males, a sex-specific result that is replicated in the LIMAA cohort of over 3400 Peruvians. Analyses of RNA-seq data further suggest an epistatic interaction on CETP expression levels between the two SNPs in multiple tissues, which also differs between males and females. We also detected interaction effects of the two SNPs with sex on cardiovascular phenotypes in the UK Biobank, in line with the sex-specific genotype associations found in Peruvians at these loci. We propose that ADCY9 and CETP coevolved during recent human evolution due to sex-specific selection, which points toward a biological link between dalcetrapib’s pharmacogene ADCY9 and its therapeutic target CETP.
    Keywords population genetics ; pharmacogenomics ; transcriptomics ; phenotype associations ; cardiovascular disease ; linkage disequilibrium ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 590
    Language English
    Publishing date 2021-10-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 lungs and inflammatory diseases with tissue inflammation

    Fan Zhang / Joseph R. Mears / Lorien Shakib / Jessica I. Beynor / Sara Shanaj / Ilya Korsunsky / Aparna Nathan / Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium / Laura T. Donlin / Soumya Raychaudhuri

    Genome Medicine, Vol 13, Iss 1, Pp 1-

    2021  Volume 17

    Abstract: Abstract Background Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help ... ...

    Abstract Abstract Background Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. Methods To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn’s disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-β) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF. Results We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α. Conclusions Our ...
    Keywords Single-cell transcriptomics ; Single-cell multi-disease tissue integration ; COVID-19 ; Inflammatory diseases ; Macrophage stimulation ; Macrophage heterogeneity ; Medicine ; R ; Genetics ; QH426-470
    Subject code 610
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: FcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity

    Vijayashree Mysore / Xavier Cullere / Joseph Mears / Florencia Rosetti / Koshu Okubo / Pei X. Liew / Fan Zhang / Iris Madera-Salcedo / Frank Rosenbauer / Richard M. Stone / Jon C. Aster / Ulrich H. von Andrian / Andrew H. Lichtman / Soumya Raychaudhuri / Tanya N. Mayadas

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 23

    Abstract: Neutrophils are versatile immune cells that may also serve as antigen-presenting cells (APC). Here the authors show that engaging FcγRs on neutrophils with immune complexes or an anti-FcγR-antigen conjugate induces neutrophil APC with comparable ... ...

    Abstract Neutrophils are versatile immune cells that may also serve as antigen-presenting cells (APC). Here the authors show that engaging FcγRs on neutrophils with immune complexes or an anti-FcγR-antigen conjugate induces neutrophil APC with comparable functions as classical dendritic cells, and with therapeutic potentials for cancer and infectious diseases.
    Keywords Science ; Q
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Tissue-Specific Enrichment of Lymphoma Risk Loci in Regulatory Elements.

    James E Hayes / Gosia Trynka / Joseph Vijai / Kenneth Offit / Soumya Raychaudhuri / Robert J Klein

    PLoS ONE, Vol 10, Iss 9, p e

    2015  Volume 0139360

    Abstract: Though numerous polymorphisms have been associated with risk of developing lymphoma, how these variants function to promote tumorigenesis is poorly understood. Here, we report that lymphoma risk SNPs, especially in the non-Hodgkin's lymphoma subtype ... ...

    Abstract Though numerous polymorphisms have been associated with risk of developing lymphoma, how these variants function to promote tumorigenesis is poorly understood. Here, we report that lymphoma risk SNPs, especially in the non-Hodgkin's lymphoma subtype chronic lymphocytic leukemia, are significantly enriched for co-localization with epigenetic marks of active gene regulation. These enrichments were seen in a lymphoid-specific manner for numerous ENCODE datasets, including DNase-hypersensitivity as well as multiple segmentation-defined enhancer regions. Furthermore, we identify putatively functional SNPs that are both in regulatory elements in lymphocytes and are associated with gene expression changes in blood. We developed an algorithm, UES, that uses a Monte Carlo simulation approach to calculate the enrichment of previously identified risk SNPs in various functional elements. This multiscale approach integrating multiple datasets helps disentangle the underlying biology of lymphoma, and more broadly, is generally applicable to GWAS results from other diseases as well.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2015-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Orgo-Seq integrates single-cell and bulk transcriptomic data to identify cell type specific-driver genes associated with autism spectrum disorder

    Elaine T. Lim / Yingleong Chan / Pepper Dawes / Xiaoge Guo / Serkan Erdin / Derek J. C. Tai / Songlei Liu / Julia M. Reichert / Mannix J. Burns / Ying Kai Chan / Jessica J. Chiang / Katharina Meyer / Xiaochang Zhang / Christopher A. Walsh / Bruce A. Yankner / Soumya Raychaudhuri / Joel N. Hirschhorn / James F. Gusella / Michael E. Talkowski /
    George M. Church

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 14

    Abstract: Cerebral organoids can be used to gain insights into neuropsychiatric disorders. Here the authors carry out RNAseq characterization from organoids derived from donors with autism spectrum disorder to identify associated cell type specific driver genes. ...

    Abstract Cerebral organoids can be used to gain insights into neuropsychiatric disorders. Here the authors carry out RNAseq characterization from organoids derived from donors with autism spectrum disorder to identify associated cell type specific driver genes.
    Keywords Science ; Q
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Towards stratified treatment of JIA

    Stephanie J.W. Shoop-Worrall / Saskia Lawson-Tovey / Lucy R. Wedderburn / Kimme L. Hyrich / Nophar Geifman / Aline Kimonyo / Alyssia McNeece / Andrew Dick / Andrew Morris / Annie Yarwood / Athimalaipet Ramanan / Bethany R. Jebson / Chris Wallace / Daniela Dastros-Pitei / Damian Tarasek / Elizabeth Ralph / Emil Carlsson / Emily Robinson / Emma Sumner /
    Fatema Merali / Fatjon Dekaj / Helen Neale / Hussein Al-Mossawi / Jacqui Roberts / Jenna F. Gritzfeld / Joanna Fairlie / John Bowes / John Ioannou / Melissa Kartawinata / Melissa Tordoff / Michael Barnes / Michael W. Beresford / Michael Stadler / Paul Martin / Rami Kallala / Sandra Ng / Samantha Smith / Sarah Clarke / Soumya Raychaudhuri / Stephen Eyre / Sumanta Mukherjee / Teresa Duerr / Thierry Sornasse / Vasiliki Alexiou / Victoria J. Burton / Wei-Yu Lin / Wendy Thomson / Zoe Wanstall

    EBioMedicine, Vol 100, Iss , Pp 104946- (2024)

    machine learning identifies subtypes in response to methotrexate from four UK cohortsResearch in context

    2024  

    Abstract: Summary: Background: Methotrexate (MTX) is the gold-standard first-line disease-modifying anti-rheumatic drug for juvenile idiopathic arthritis (JIA), despite only being either effective or tolerated in half of children and young people (CYP). To ... ...

    Abstract Summary: Background: Methotrexate (MTX) is the gold-standard first-line disease-modifying anti-rheumatic drug for juvenile idiopathic arthritis (JIA), despite only being either effective or tolerated in half of children and young people (CYP). To facilitate stratified treatment of early JIA, novel methods in machine learning were used to i) identify clusters with distinct disease patterns following MTX initiation; ii) predict cluster membership; and iii) compare clusters to existing treatment response measures. Methods: Discovery and verification cohorts included CYP who first initiated MTX before January 2018 in one of four UK multicentre prospective cohorts of JIA within the CLUSTER consortium. JADAS components (active joint count, physician (PGA) and parental (PGE) global assessments, ESR) were recorded at MTX start and over the following year.Clusters of MTX ‘response’ were uncovered using multivariate group-based trajectory modelling separately in discovery and verification cohorts. Clusters were compared descriptively to ACR Pedi 30/90 scores, and multivariate logistic regression models predicted cluster-group assignment. Findings: The discovery cohorts included 657 CYP and verification cohorts 1241 CYP. Six clusters were identified: Fast improvers (11%), Slow Improvers (16%), Improve-Relapse (7%), Persistent Disease (44%), Persistent PGA (8%) and Persistent PGE (13%), the latter two characterised by improvement in all features except one. Factors associated with clusters included ethnicity, ILAR category, age, PGE, and ESR scores at MTX start, with predictive model area under the curve values of 0.65–0.71. Singular ACR Pedi 30/90 scores at 6 and 12 months could not capture speeds of improvement, relapsing courses or diverging disease patterns. Interpretation: Six distinct patterns following initiation of MTX have been identified using methods in artificial intelligence. These clusters demonstrate the limitations in traditional yes/no treatment response assessment (e.g., ACRPedi30) and can form the basis ...
    Keywords Juvenile idiopathic arthritis ; Machine learning ; Treatment outcome ; Epidemiology ; Methotrexate ; Medicine ; R ; Medicine (General) ; R5-920
    Subject code 310
    Language English
    Publishing date 2024-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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