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

Molly Went ; Amit Sud

; Asta Försti ; Britt-Marie Halvarsson ; Niels Weinhold ; Scott Kimber ; Mark van Duin ; Gudmar Thorleifsson ; Amy Holroyd ; David C Johnson

; +60 more... Ni Li ; Giulia Orlando ; Philip J Law

; Mina Ali ; Bowang Chen ; Jonathan S Mitchell ; Daniel F Gudbjartsson

; Rowan Kuiper ; Owen W Stephens ; Uta Bertsch ; Peter Broderick

; Chiara Campo ; Obul R Bandapalli

; Hermann Einsele ; Walter A Gregory ; Urban Gullberg ; Jens Hillengass ; Per Hoffmann ; Graham H Jackson ; Karl-Heinz Jöckel ; Ellinor Johnsson ; Sigurður Y Kristinsson ; Ulf-Henrik Mellqvist ; Hareth Nahi ; Douglas Easton

; Paul Pharoah

; Alison Dunning ; Julian Peto

; Federico Canzian

; Anthony Swerdlow ; Rosalind A Eeles

; ZSofia Kote-Jarai ; Kenneth Muir

; Nora Pashayan

; Jolanta Nickel ; Markus M Nöthen ; Thorunn Rafnar ; Fiona M Ross ; Miguel Inacio da Silva Filho ; Hauke Thomsen ; Ingemar Turesson ; Annette Vangsted ; Niels Frost Andersen ; Anders Waage ; Brian A Walker ; Anna-Karin Wihlborg ; Annemiek Broyl ; Faith E Davies ; Unnur Thorsteinsdottir ; Christian Langer ; Markus Hansson

; Hartmut Goldschmidt ; Martin Kaiser ; Pieter Sonneveld ; Kari Stefansson ; Gareth J Morgan ; Kari Hemminki ; Björn Nilsson ; Richard S Houlston

; PRACTICAL consortium ; (2018) Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nature communications, 9 (1). 3707-. ISSN 2041-1723 DOI: 10.1038/s41467-018-04989-w

Copy

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.