Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk Journal Article


Authors: Waller, R. G.; Darlington, T. M.; Wei, X.; Madsen, M. J.; Thomas, A.; Curtin, K.; Coon, H.; Rajamanickam, V.; Musinsky, J.; Jayabalan, D.; Atanackovic, D.; Rajkumar, S. V.; Kumar, S.; Slager, S.; Middha, M.; Galia, P.; Demangel, D.; Salama, M.; Joseph, V.; McKay, J.; Offit, K.; Klein, R. J.; Lipkin, S. M.; Dumontet, C.; Vachon, C. M.; Camp, N. J.
Article Title: Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk
Abstract: The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance–a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits. © 2018 Waller et al.
Keywords: clinical article; controlled study; gene sequence; single nucleotide polymorphism; gene deletion; cancer risk; gene; dna repair; multiple myeloma; serine; genetic variation; risk assessment; gene mapping; enzyme regulation; endonuclease; monoclonal immunoglobulinemia; glutamic acid; genetic code; glutamine; methionine; chromatin assembly and disassembly; genetic heterogeneity; pedigree analysis; exome; human; article; usp45 gene
Journal Title: PLoS Genetics
Volume: 14
Issue: 2
ISSN: 1553-7390
Publisher: Public Library of Science  
Date Published: 2018-02-01
Start Page: e1007111
Language: English
DOI: 10.1371/journal.pgen.1007111
PROVIDER: scopus
PMCID: PMC5794067
PUBMED: 29389935
DOI/URL:
Notes: Jacob Musinsky's first name is incorrectly listed as Justin in the original publication -- Article -- Export Date: 2 April 2018 -- Source: Scopus
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MSK Authors
  1. Kenneth Offit
    509 Offit
  2. Vijai Joseph
    117 Joseph