TY - JOUR
T1 - Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk
AU - Waller, Rosalie G.
AU - Darlington, Todd M.
AU - Wei, Xiaomu
AU - Madsen, Michael J.
AU - Thomas, Alun
AU - Curtin, Karen
AU - Coon, Hilary
AU - Rajamanickam, Venkatesh
AU - Musinsky, Justin
AU - Jayabalan, David
AU - Atanackovic, Djordje
AU - Rajkumar, S. Vincent
AU - Kumar, Shaji
AU - Slager, Susan
AU - Middha, Mridu
AU - Galia, Perrine
AU - Demangel, Delphine
AU - Salama, Mohamed
AU - Joseph, Vijai
AU - McKay, James
AU - Offit, Kenneth
AU - Klein, Robert J.
AU - Lipkin, Steven M.
AU - Dumontet, Charles
AU - Vachon, Celine M.
AU - Camp, Nicola J.
N1 - Publisher Copyright:
© 2018 Waller et al.
PY - 2018/2
Y1 - 2018/2
N2 - 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.
AB - 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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U2 - 10.1371/journal.pgen.1007111
DO - 10.1371/journal.pgen.1007111
M3 - Article
C2 - 29389935
AN - SCOPUS:85043303673
SN - 1553-7390
VL - 14
JO - PLoS genetics
JF - PLoS genetics
IS - 2
M1 - e1007111
ER -