Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
Authors: Went Molly , Sud Amit , Försti Asta , Halvarsson Britt-Marie , Weinhold Niels , Kimber Scott , van Duin Mark , Thorleifsson Gudmar , Holroyd Amy , Johnson David C. , Li Ni , Orlando Giulia , Law Philip J. , Ali Mina , Chen Bowang , Mitchell Jonathan S. , Gudbjartsson Daniel F. , Kuiper Rowan , Stephens Owen W. , Bertsch Uta , Broderick Peter , Campo Chiara , Bandapalli Obul R , Einsele Hermann , Gregory Walter A. , Gullberg Urban , Hillengass Jens , Hoffmann Per , Jackson Graham H. , Jöckel Karl-Heinz , Johnsson Ellinor , Kristinsson Sigurður Y. , Mellqvist Ulf-Henrik , Nahi Hareth , Easton Douglas , Pharoah Paul , Dunning Alison , Peto Julian , Canzian Federico , Swerdlow Anthony , Eeles Rosalind A. , Kote-Jarai ZSofia , Muir Kenneth , Pashayan Nora , Nickel Jolanta , Nöthen Markus M. , Rafnar Thorunn , Ross Fiona M. , da Silva Filho Miguel Inacio , Thomsen Hauke , Turesson Ingemar , Vangsted Annette , Andersen Niels Frost , Waage Anders , Walker Brian A. , Wihlborg Anna-Karin , Broyl Annemiek , Davies Faith E. , Thorsteinsdottir Unnur , Langer Christian , Hansson Markus , Goldschmidt Hartmut , Kaiser Martin , Sonneveld Pieter , Stefansson Kari , Morgan Gareth J. , Hemminki Kari , Nilsson Björn , Houlston Richard S. ,   The PRACTICAL consortium, Henderson Brian E. , Haiman Christopher A. , Benlloch Sara , Schumacher Fredrick R. , Olama Ali Amin Al , Berndt Sonja I. , Conti David V. , Wiklund Fredrik , Chanock Stephen , Stevens Victoria L. , Tangen Catherine M. , Batra Jyotsna , Clements Judith , Gronberg Henrik , Schleutker Johanna , Albanes Demetrius , Weinstein Stephanie , Wolk Alicja , West Catharine , Mucci Lorelei , Cancel-Tassin Géraldine , Koutros Stella , Sorensen Karina Dalsgaard , Grindedal Eli Marie , Neal David E. , Hamdy Freddie C. , Donovan Jenny L. , Travis Ruth C. , Hamilton Robert J. , Ingles Sue Ann , Rosenstein Barry , Lu Yong-Jie , Giles Graham G. , Kibel Adam S. , Vega Ana , Kogevinas Manolis , Penney Kathryn L. , Park Jong Y. , Stanford Janet L. , Cybulski Cezary , Nordestgaard Børge G. , Brenner Hermann , Maier Christiane , Kim Jeri , John Esther M. , Teixeira Manuel R. , Neuhausen Susan L. , De Ruyck Kim , Razack Azad , Newcomb Lisa F. , Lessel Davor , Kaneva Radka , Usmani Nawaid , Claessens Frank , Townsend Paul A. , Gago-Dominguez Manuela , Roobol Monique J. , Menegaux Florence , Khaw Kay-Tee , Cannon-Albright Lisa , Pandha Hardev , Thibodeau Stephen N. 
Published: September 2018

AbstractGenome-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.