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

Rosalie G. Waller, Todd M. Darlington, Xiaomu Wei, Michael J. Madsen, Alun Thomas, Karen Curtin, Hilary Coon, Venkatesh Rajamanickam, Justin Musinsky, David Jayabalan, Djordje Atanackovic, S Vincent Rajkumar, Shaji K Kumar, Susan L Slager, Mridu Middha, Perrine Galia, Delphine Demangel, Mohamed Salama, Vijai Joseph, James McKayKenneth Offit, Robert J. Klein, Steven M. Lipkin, Charles Dumontet, Celine M Vachon, Nicola J. Camp

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1007111
JournalPLoS Genetics
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

myeloma
Chromatin Assembly and Disassembly
Pedigree
DNA repair
Multiple Myeloma
DNA Repair
pedigree
repair
chromatin
DNA
Exome
genomics
Paraproteinemias
Genetic Heterogeneity
gene
Endonucleases
Genes
inheritance (genetics)
genes
genome

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Waller, R. G., Darlington, T. M., Wei, X., Madsen, M. J., Thomas, A., Curtin, K., ... Camp, N. J. (2018). Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk. PLoS Genetics, 14(2), [e1007111]. https://doi.org/10.1371/journal.pgen.1007111

Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk. / Waller, Rosalie G.; Darlington, Todd M.; Wei, Xiaomu; Madsen, Michael J.; Thomas, Alun; Curtin, Karen; Coon, Hilary; Rajamanickam, Venkatesh; Musinsky, Justin; Jayabalan, David; Atanackovic, Djordje; Rajkumar, S Vincent; Kumar, Shaji K; Slager, Susan L; Middha, Mridu; Galia, Perrine; Demangel, Delphine; Salama, Mohamed; Joseph, Vijai; McKay, James; Offit, Kenneth; Klein, Robert J.; Lipkin, Steven M.; Dumontet, Charles; Vachon, Celine M; Camp, Nicola J.

In: PLoS Genetics, Vol. 14, No. 2, e1007111, 01.02.2018.

Research output: Contribution to journalArticle

Waller, RG, Darlington, TM, Wei, X, Madsen, MJ, Thomas, A, Curtin, K, Coon, H, Rajamanickam, V, Musinsky, J, Jayabalan, D, Atanackovic, D, Rajkumar, SV, Kumar, SK, Slager, SL, Middha, M, Galia, P, Demangel, D, Salama, M, Joseph, V, McKay, J, Offit, K, Klein, RJ, Lipkin, SM, Dumontet, C, Vachon, CM & Camp, NJ 2018, 'Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk', PLoS Genetics, vol. 14, no. 2, e1007111. https://doi.org/10.1371/journal.pgen.1007111
Waller RG, Darlington TM, Wei X, Madsen MJ, Thomas A, Curtin K et al. Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk. PLoS Genetics. 2018 Feb 1;14(2). e1007111. https://doi.org/10.1371/journal.pgen.1007111
Waller, Rosalie G. ; Darlington, Todd M. ; Wei, Xiaomu ; Madsen, Michael J. ; Thomas, Alun ; Curtin, Karen ; Coon, Hilary ; Rajamanickam, Venkatesh ; Musinsky, Justin ; Jayabalan, David ; Atanackovic, Djordje ; Rajkumar, S Vincent ; Kumar, Shaji K ; Slager, Susan L ; Middha, Mridu ; Galia, Perrine ; Demangel, Delphine ; Salama, Mohamed ; Joseph, Vijai ; McKay, James ; Offit, Kenneth ; Klein, Robert J. ; Lipkin, Steven M. ; Dumontet, Charles ; Vachon, Celine M ; Camp, Nicola J. / Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk. In: PLoS Genetics. 2018 ; Vol. 14, No. 2.
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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.",
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AU - Demangel, Delphine

AU - Salama, Mohamed

AU - Joseph, Vijai

AU - McKay, James

AU - Offit, Kenneth

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