title: Search for rare protein altering variants influencing susceptibility to multiple myeloma.
abstract: 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.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK.|Centre of Bioinformatics and Systems Biology, Department of Life Sciences, Imperial College London, London, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Scales
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chubb
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Dobbins
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK.|Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Johnson
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Ni
authors.initials: N
authors.lastname: Li
authors.affiliation: Centre of Bioinformatics and Systems Biology, Department of Life Sciences, Imperial College London, London, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sternberg
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Neils
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Caleb
authors.initials: C
authors.lastname: Stein
authors.affiliation: Department of Haematology, Newcastle University, Newcastle, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Jackson
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Walker
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Wardell
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK.|Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
mesh_terms: D000368:Aged; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D018628:Gene Dosage; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008297:Male; D008938:Mitosis; D009101:Multiple Myeloma / Q000235:genetics* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D059467:Transcriptome
chemical_list: C502735:KIF18A protein, human; D016547:Kinesins
keywords: exome sequencing; inherited risk; multiple myeloma