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A novel pedigree analysis has uncovered two genes with links to inherited multiple myeloma risk.

Researchers from the United States and France used an updated version of Shared Genomic Segment to narrow in on commonly altered areas of the genomes of families prone to multiple-myeloma – or “high-risk pedigrees.”

Family-based studies have helped uncovered rare, causal mutations behind single-gene conditions in multiple myeloma. However, it can be more difficult to identify complex trait genetics using high-risk pedigree mapping alone.

“While high-risk pedigrees have been successful for relatively simple traits, genetic heterogeneity remains a major obstacle that reduced the effectiveness of high-risk pedigrees for gene mapping in complex traits,” Nicola Camp, PhD, University of Utah School of Medicine, and colleagues wrote in their study, published in PLOS Genetics (online February 1, 2018; doi:10.1371/journal.pgen.1007111).

By utilizing Illumina OmniExpress high-density SNP arrays, researchers sequenced patients from 11 multiple myeloma high-risk pedigrees and applied Shared Genomic Segment to find the shared regions of the genome on chromosomes 6 and 1 with likely associations with multiple myeloma. Exome sequence data from 28 individuals—along with 126 exomes from a broader set of 44 multiple myeloma multinational pedigrees—were folded in to identify potentially deleterious mutations in two genes of potential interest: USP45 and ARID1A.

Results led researchers to conclude that exome sequencing of these genes reveal likely-damaging variants inherited in families at high-risk for multiple myeloma, suggesting that these genes likely play a role in the development of multiple myeloma.


"Our myeloma findings demonstrate our high-risk pedigree method can identify genetic regions of interest in large, high-risk pedigrees that are also relevant to smaller nuclear families and overall disease risk," wrote Dr Camp and colleagues. “We have developed a strategy for gene mapping in complex traits that accounts for heterogeneity within high-risk pedigrees and formally corrects for multiple testing to allow for statistically rigorous discovery."—Zachary Bessette