Search for rare protein altering variants influencing susceptibility to multiple myeloma
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Matthew Scales1,2, Daniel Chubb1, Sara E. Dobbins1, David C. Johnson1,3, Ni Li1, Michael J. Sternberg2, Neils Weinhold4, Caleb Stein4, Graham Jackson5, Faith E. Davies4, Brian A. Walker4, Christopher P. Wardell4, Richard S. Houlston1,3 and Gareth J. Morgan4
1Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK
2Centre of Bioinformatics and Systems Biology, Department of Life Sciences, Imperial College London, London, UK
3Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey, UK
4The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
5Department of Haematology, Newcastle University, Newcastle, UK
Richard S. Houlston, email: email@example.com
Keywords: multiple myeloma, inherited risk, exome sequencing
Received: September 30, 2016 Accepted: January 28, 2017 Published: March 03, 2017
The genetic basis underlying the inherited risk of developing multiple myeloma (MM) is largely unknown. To examine the impact of rare protein altering variants on the risk of developing MM we analyzed high-coverage exome sequencing data on 513 MM cases and 1,569 healthy controls, performing both single variant and gene burden tests. We did not identify any recurrent coding low-frequency alleles (1–5%) with moderate effect that were statistically associated with MM. In a gene burden analysis we did however identify a promising relationship between variation in the marrow kinetochore microtubule stromal gene KIF18A, which plays a role in control mitotic chromosome positioning dynamics, and risk of MM (P =3.6x10−6). Further analysis showed KIF18A displays a distinct pattern of expression across molecular subgroups of MM as well as being associated with patient survival. Our results inform future study design and provide a resource for contextualizing the impact of candidate MM susceptibility genes.
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