Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma.

Nat Commun

Authors	Molly Went Amit Sud Asta Försti Britt-Marie Halvarsson Niels Weinhold Scott Kimber Mark van Duin Gudmar Thorleifsson Amy Holroyd David Johnson Ni Li Giulia Orlando Philip Law Mina Ali Bowang Chen Jonathan Mitchell Daniel Gudbjartsson Rowan Kuiper Owen Stephens Uta Bertsch Peter Broderick Chiara Campo Obul Bandapalli Hermann Einsele Walter Gregory Urban Gullberg Jens Hillengass Per Hoffmann Graham Jackson Karl-Heinz Jöckel Ellinor Johnsson Sigurður Kristinsson Ulf-Henrik Mellqvist Hareth Nahi Douglas Easton Paul Pharoah Alison Dunning Julian Peto Federico Canzian Anthony Swerdlow Rosalind Eeles Zsofia Kote-Jarai Kenneth Muir Nora Pashayan Jolanta Nickel Markus Nöthen Thorunn Rafnar Fiona Ross Miguel Filho Hauke Thomsen Ingemar Turesson Annette Vangsted Niels Andersen Anders Waage Brian Walker Anna-Karin Wihlborg Annemiek Broyl Faith Davies Unnur Thorsteinsdottir Christian Langer Markus Hansson Hartmut Goldschmidt Martin Kaiser Pieter Sonneveld Kari Stefansson Gareth Morgan Kari Hemminki Björn Nilsson Richard Houlston PRACTICAL Consortium
Keywords	Female Humans Male Gene Expression Regulation Chromatin Immunoprecipitation Genetic Predisposition to Disease Genotype Genome-Wide Association Study Polymorphism, Single Nucleotide Chromatin Quantitative Trait Loci Promoter Regions, Genetic Bayes Theorem Multiple Myeloma Risk Quality Control Whites
Abstract	Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.
Year of Publication	2018
Journal	Nat Commun
Volume	9
Issue	1
Pages	3707
Date Published	2018 09 13
ISSN	2041-1723
DOI	10.1038/s41467-018-04989-w
PubMed ID	30213928
PubMed Central ID	PMC6137048
Links	Google Scholar PubMed DOI
Grant list	P20 GM125503 / GM / NIGMS NIH HHS / United States U01 CA188392 / CA / NCI NIH HHS / United States HHSN268201200008C / HL / NHLBI NIH HHS / United States U19 CA148537 / CA / NCI NIH HHS / United States 14136 / CRUK_ / Cancer Research UK / United Kingdom Wellcome Trust / United Kingdom P01 CA055819 / CA / NCI NIH HHS / United States HHSN268201200008I / HL / NHLBI NIH HHS / United States

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