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      Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens

      1 , 1 , 2 , 3 , 1 , 4 , 5 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 2 , 6 , 7 , 2 , 3 , 8 , 8 , 8 , 9 , 10 , 9 , 10 , 11 , 11 , 12 , 12 , 12 , 13 , 14 , 15 , 16 , 17 , 17 , 17 , 17 , 18 , 18 , 18 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 24 , 25 , 26 , 27 , 27 , 28 , 28 , 29 , 30 , 31 , 32 , 32 , 33 , 34 , 33 , 33 , 35 , 36 , 35 , 36 , 37 , 37 , 38 , 39 , 39 , 40 , 41 , 42 , 43 , 44 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 51 , 52 , 53 , 54 , 53 , 54 , 55 , 56 , 57 , 58 , 42 , 43 , 48 , 8 , 4 , 59 , 1

      Nature genetics

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          Abstract

          We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six novel genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geo-spatial distribution of risk alleles is highly suggestive of multi-locus adaptation and the genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.

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          Most cited references 105

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          Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

          Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.
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            PLINK: a tool set for whole-genome association and population-based linkage analyses.

            Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
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              Is Open Access

              ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data

              High-throughput sequencing platforms are generating massive amounts of genetic variation data for diverse genomes, but it remains a challenge to pinpoint a small subset of functionally important variants. To fill these unmet needs, we developed the ANNOVAR tool to annotate single nucleotide variants (SNVs) and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP. ANNOVAR can utilize annotation databases from the UCSC Genome Browser or any annotation data set conforming to Generic Feature Format version 3 (GFF3). We also illustrate a ‘variants reduction’ protocol on 4.7 million SNVs and indels from a human genome, including two causal mutations for Miller syndrome, a rare recessive disease. Through a stepwise procedure, we excluded variants that are unlikely to be causal, and identified 20 candidate genes including the causal gene. Using a desktop computer, ANNOVAR requires ∼4 min to perform gene-based annotation and ∼15 min to perform variants reduction on 4.7 million variants, making it practical to handle hundreds of human genomes in a day. ANNOVAR is freely available at http://www.openbioinformatics.org/annovar/ .
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                25 September 2014
                12 October 2014
                November 2014
                01 May 2015
                : 46
                : 11
                : 1187-1196
                Affiliations
                [1 ]Dept. of Medicine, Div. of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
                [2 ]Div. of Nephrology, Azienda Ospedaliera Spedali Civili of Brescia, Montichiari Hospital, Univ of Brescia, Brescia, Italy
                [3 ]Dept. of Medical and Surgical Specialties, Radiological Sciences, University of Brescia, Brescia, Italy
                [4 ]Dept. of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA
                [5 ]Dept. of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
                [6 ]Prenatal Diagnosis Unit, Department of Obstetrics and Gynecology, University of Brescia, Brescia, Italy
                [7 ]Div. of Nephrology, Azienda Ospedaliera Spedali Civili of Brescia, Spedali Civili Hospital, Univ of Brescia, Brescia, Italy
                [8 ]Renal Div., DMCO, San Paolo Hospital, School of Medicine, University of Milan, Milan, Italy
                [9 ]Immunogenetics and Biology of Transplantation, Città della Salute e della Scienza, University Hospital of Turin, Italy
                [10 ]Medical Genetics, Dept. of Medical Sciences, University of Torino, Torino, Italy
                [11 ]Nephrology and Dialysis Unit, Ospedali di Cirié e Chivasso, Cirié, Torino, Italy
                [12 ]Nephrology, Dialysis, and Transplantation Unit, Regina Margheritra Hospital, Torino, Italy
                [13 ]Div. of Nephrology and Renal Transplantation, Carreggi Hospital, Florence, Italy
                [14 ]Dept. of Medicine, University of Calgary, Calgary, Canada
                [15 ]Dept. of Community Health Sciences, University of Calgary, Calgary, Canada
                [16 ]Div. of Nephrology Dialysis and Transplantation, Azienda Ospedaliero Universitaria Policlinico di Modena, Università di Modena e Reggio Emilia, Italy
                [17 ]Div. of Nephrology, Dialysis and Transplantation, Giannina Gaslini Institute, Genova, Italy
                [18 ]Div. of Nephrology, Azienda Ospedaliero-Universitaria and Chair of Nephrology, University of Parma, Parma, Italy
                [19 ]Div. of Nephrology, Dialysis and Renal Transpantation, Riuniti Hospital, Ancona, Italy
                [20 ]Div. of Nephrology and Dialysis, Gorizia Hospital, Gorizia, Italy
                [21 ]Div. of Nephrology, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Trieste, Trieste, Italy
                [22 ]CP Humanitas Clinical and Research Center, Milan, Italy
                [23 ]Div. of Nephrology and Dialysis, Infermi Hospital, Rimini, Italy
                [24 ]Div. of Nephrology, Cannizzaro Hospital, Catania, Italy
                [25 ]Div. of Nephology and Dialysis, Chair of Nephrology, University of Messina, Azienda Ospedaliero-Universitaria Policlinico, Messina, Italy
                [26 ]Dept. of Nephrology and Dialysis, G. Brotzu Hospital, Cagliari, Italy
                [27 ]Nephrology and Dialysis, Hospital of Viterbo, Viterbo, Italy
                [28 ]Div. of Nephrology and Dialysis, Sandro Pertini Hospital, Rome, Italy
                [29 ]Dept. of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
                [30 ]Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
                [31 ]Dept. of Nephrology, Second University of Naples, Naples, Italy
                [32 ]Dept. of Nephrology, 1st Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic
                [33 ]Dept. of Nephrology, RWTH University of Aachen, Aachen, Germany
                [34 ]Kidney Diseases Research, Bayer Pharma AG, Wuppertal, Germany
                [35 ]Nephrology Center, Medical Faculty, University of Pécs, Pécs, Hungary
                [36 ]Second Dept. of Internal Medicine, Medical Faculty, University of Pécs, Pécs, Hungary
                [37 ]Dept. of Immunology, Transplantology, and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
                [38 ]Children’s Hospital, Krysiewicza 7/8, Poznań, Poland
                [39 ]Dept. of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland
                [40 ]Dept. of Nephrology, Transplantology, and Internal Medicine, Poznan Medical University, Poznan, Poland
                [41 ]University College London-Centre for Nephrology, Royal Free Hospital Pond Street, London
                [42 ]The John Walls Renal Unit, University Hospitals of Leicester, Leicester, United Kingdom
                [43 ]Dept. of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom
                [44 ]Nephrology, Dialysis, and Renal Transplantation Dept., University North Hospital, Saint Etienne, France
                [45 ]Service de Néphrologie Transplantation Adultes, Hôpital Necker - Enfants Malades, Paris, France
                [46 ]INSERM, Institut Necker Enfants Malades, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
                [47 ]Centre National de Génotypage, CEA, Institut de Génomique, Evry, France
                [48 ]INSERM, Centre for Research in Epidemiology and Population Health, Villejuif, France and University Paris-Sud, Villejuif, France
                [49 ]III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
                [50 ]Division of Nephrology, Dept. of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan
                [51 ]Division of Clinical Nephrology and Rheumatology, Niigata University, Niigata, Japan
                [52 ]Division of Nephrology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
                [53 ]Dept. of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
                [54 ]Renal Div., Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
                [55 ]Div. of Pediatric Nephrology, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
                [56 ]Children’s Foundation Research Center, Le Bonheur Children’s Hospital, Memphis, Tennessee, USA
                [57 ]Dept. of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
                [58 ]Dept. of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
                [59 ]Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA
                Author notes
                Corresponding Authors: Ali Gharavi, MD, Department of Medicine, Division of Nephrology, Columbia University, 1150 St Nicholas Ave, Russ Berrie Pavilion #413, New York, NY 10032, USA, Tel: 212-851-5556, Fax: 212-851-5461, ag2239@ 123456columbia.edu . Richard P. Lifton, MD, PhD, Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street, TAC S-341D, New Haven, CT 06520, USA, Tel: 203-737-4420, Fax: 203-785-7560, richard.lifton@ 123456yale.edu
                Article
                NIHMS630801
                10.1038/ng.3118
                4213311
                25305756
                Categories
                Article

                Genetics

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