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

• Published in: PLoS genetics Vol. 14; no. 2; p. e1007111
• Main Authors: 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, Slager, Susan, 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-02-2018; Public Library of Science (PLoS)
• Subjects: Analysis; Benign monoclonal gammopathy; Biology and life sciences; Cancer; Case-Control Studies; Chromatin; Chromatin Assembly and Disassembly - genetics; Chromatin remodeling; Databases, Genetic; DNA Mutational Analysis; DNA repair; DNA Repair - genetics; Endonuclease; Exome sequencing; Family; Female; Funding; Gene mapping; Genes; Genetic Predisposition to Disease; Genetic Variation - drug effects; Genome-Wide Association Study; Genomes; Genomics; Heredity; Humans; Male; Medicine; Medicine and Health Sciences; Methods; Multiple myeloma; Multiple Myeloma - genetics; Mutation; Pedigree; People and places; Research and Analysis Methods; Software; Supervision; Utah; New York; Minnesota; France; United States > US
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1007111

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.