title: Tissue-Specific Enrichment of Lymphoma Risk Loci in Regulatory Elements.
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.
authors.affiliation: Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Cell and Developmental Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York, United States of America; Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: James E
authors.initials: JE
authors.lastname: Hayes
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.affiliation: Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Vijai
authors.affiliation: Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Klein
mesh_terms: D000465:Algorithms; D056426:Genetic Loci; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D015810:Linkage Disequilibrium; D009010:Monte Carlo Method; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D050436:Regulatory Elements, Transcriptional; D012307:Risk Factors