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

Lookup NU author(s): Professor Graham Jackson

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Abstract

© 2018, The Author(s). 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.

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Author(s): Went M, Sud A, Forsti A, Halvarsson B-M, Weinhold N, Kimber S, van Duin M, Thorleifsson G, Holroyd A, Johnson DC, Li N, Orlando G, Law PJ, Ali M, Chen B, Mitchell JS, Gudbjartsson DF, Kuiper R, Stephens OW, Bertsch U, Broderick P, Campo C, Bandapalli OR, Einsele H, Gregory WA, Gullberg U, Hillengass J, Hoffmann P, Jackson GH, Jockel K-H, Johnsson E, Kristinsson SY, Mellqvist U-H, Nahi H, Easton D, Pharoah P, Dunning A, Peto J, Canzian F, Swerdlow A, Eeles RA, Kote-Jarai ZS, Muir K, Pashayan N, Nickel J, Nothen MM, Rafnar T, Ross FM, da Silva Filho MI, Thomsen H, Turesson I, Vangsted A, Andersen NF, Waage A, Walker BA, Wihlborg A-K, Broyl A, Davies FE, Thorsteinsdottir U, Langer C, Hansson M, Goldschmidt H, Kaiser M, Sonneveld P, Stefansson K, Morgan GJ, Hemminki K, Nilsson B, Houlston RS, Henderson BE, Haiman CA, Benlloch S, Schumacher FR, Olama AAA, Berndt SI, Conti DV, Wiklund F, Chanock S, Stevens VL, Tangen CM, Batra J, Clements J, Gronberg H, Schleutker J, Albanes D, Weinstein S, Wolk A, West C, Mucci L, Cancel-Tassin G, Koutros S, Sorensen KD, Grindedal EM, Neal DE, Hamdy FC, Donovan JL, Travis RC, Hamilton RJ, Ingles SA, Rosenstein B, Lu Y-J, Giles GG, Kibel AS, Vega A, Kogevinas M, Penney KL, Park JY, Stanford JL, Cybulski C, Nordestgaard BG, Brenner H, Maier C, Kim J, John EM, Teixeira MR, Neuhausen SL, De Ruyck K, Razack A, Newcomb LF, Lessel D, Kaneva R, Usmani N, Claessens F, Townsend PA, Dominguez MG, Roobol MJ, Menegaux F, Khaw K-T, Cannon-Albright L, Pandha H, Thibodeau SN

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2018

Volume: 9

Issue: 1

Online publication date: 13/09/2018

Acceptance date: 06/06/2018

Date deposited: 01/10/2018

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41467-018-04989-w

DOI: 10.1038/s41467-018-04989-w

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