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Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma

Inherited genetic susceptibility to multiple myeloma has been investigated in a number of studies. Although 23 individual risk loci have been identified, much of the genetic heritability remains unknown. Here we carried out genome-wide interaction analyses on two European cohorts accounting for 3,99...

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Autores principales: Chattopadhyay, Subhayan, Thomsen, Hauke, Yadav, Pankaj, da Silva Filho, Miguel Inacio, Weinhold, Niels, Nöthen, Markus M., Hoffman, Per, Bertsch, Uta, Huhn, Stefanie, Morgan, Gareth J., Goldschmidt, Hartmut, Houlston, Richard, Hemminki, Kari, Försti, Asta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399257/
https://www.ncbi.nlm.nih.gov/pubmed/30854481
http://dx.doi.org/10.1038/s42003-019-0329-2
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author Chattopadhyay, Subhayan
Thomsen, Hauke
Yadav, Pankaj
da Silva Filho, Miguel Inacio
Weinhold, Niels
Nöthen, Markus M.
Hoffman, Per
Bertsch, Uta
Huhn, Stefanie
Morgan, Gareth J.
Goldschmidt, Hartmut
Houlston, Richard
Hemminki, Kari
Försti, Asta
author_facet Chattopadhyay, Subhayan
Thomsen, Hauke
Yadav, Pankaj
da Silva Filho, Miguel Inacio
Weinhold, Niels
Nöthen, Markus M.
Hoffman, Per
Bertsch, Uta
Huhn, Stefanie
Morgan, Gareth J.
Goldschmidt, Hartmut
Houlston, Richard
Hemminki, Kari
Försti, Asta
author_sort Chattopadhyay, Subhayan
collection PubMed
description Inherited genetic susceptibility to multiple myeloma has been investigated in a number of studies. Although 23 individual risk loci have been identified, much of the genetic heritability remains unknown. Here we carried out genome-wide interaction analyses on two European cohorts accounting for 3,999 cases and 7,266 controls and characterized genetic susceptibility to multiple myeloma with subsequent meta-analysis that discovered 16 unique interacting loci. These risk loci along with previously known variants explain 17% of the heritability in liability scale. The genes associated with the interacting loci were found to be enriched in transforming growth factor beta signaling and circadian rhythm regulation pathways suggesting immunoglobulin trait modulation, T(H)17 cell differentiation and bone morphogenesis as mechanistic links between the predisposition markers and intrinsic multiple myeloma biology. Further tissue/cell-type enrichment analysis associated the discovered genes with hemic-immune system tissue types and immune-related cell types indicating overall involvement in immune response.
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spelling pubmed-63992572019-03-08 Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma Chattopadhyay, Subhayan Thomsen, Hauke Yadav, Pankaj da Silva Filho, Miguel Inacio Weinhold, Niels Nöthen, Markus M. Hoffman, Per Bertsch, Uta Huhn, Stefanie Morgan, Gareth J. Goldschmidt, Hartmut Houlston, Richard Hemminki, Kari Försti, Asta Commun Biol Article Inherited genetic susceptibility to multiple myeloma has been investigated in a number of studies. Although 23 individual risk loci have been identified, much of the genetic heritability remains unknown. Here we carried out genome-wide interaction analyses on two European cohorts accounting for 3,999 cases and 7,266 controls and characterized genetic susceptibility to multiple myeloma with subsequent meta-analysis that discovered 16 unique interacting loci. These risk loci along with previously known variants explain 17% of the heritability in liability scale. The genes associated with the interacting loci were found to be enriched in transforming growth factor beta signaling and circadian rhythm regulation pathways suggesting immunoglobulin trait modulation, T(H)17 cell differentiation and bone morphogenesis as mechanistic links between the predisposition markers and intrinsic multiple myeloma biology. Further tissue/cell-type enrichment analysis associated the discovered genes with hemic-immune system tissue types and immune-related cell types indicating overall involvement in immune response. Nature Publishing Group UK 2019-03-04 /pmc/articles/PMC6399257/ /pubmed/30854481 http://dx.doi.org/10.1038/s42003-019-0329-2 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chattopadhyay, Subhayan
Thomsen, Hauke
Yadav, Pankaj
da Silva Filho, Miguel Inacio
Weinhold, Niels
Nöthen, Markus M.
Hoffman, Per
Bertsch, Uta
Huhn, Stefanie
Morgan, Gareth J.
Goldschmidt, Hartmut
Houlston, Richard
Hemminki, Kari
Försti, Asta
Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma
title Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma
title_full Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma
title_fullStr Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma
title_full_unstemmed Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma
title_short Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma
title_sort genome-wide interaction and pathway-based identification of key regulators in multiple myeloma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399257/
https://www.ncbi.nlm.nih.gov/pubmed/30854481
http://dx.doi.org/10.1038/s42003-019-0329-2
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