Changes in genes involved in DNA repair and packaging linked to risk of multiple myeloma
Researchers have identified two gene regions that contribute to multiple myeloma, an inherited cancer that occurs in bone marrow, through a new method that makes use of human disease pedigrees. Nicola Camp and Rosalie Waller of the Huntsman Cancer Institute at the University of Utah, and colleagues, report their findings February 1st, 2018, in PLOS Genetics.
Human pedigrees can help geneticists to track diseases through different branches of a family tree and pinpoint the mutations that are responsible. This process is straightforward in diseases caused by a mutation in a single gene, but for complex diseases, which involve multiple genes, the use of pedigrees has not been so effective. In the current study, researchers developed a new method to analyze high-risk pedigrees (large, multi-generational families with more affected members than would be expected by chance) to identify shared regions of the genome that likely harbor disease-causing genes. They applied the method using pedigrees from 11 Utah families at risk of multiple myeloma, a complex, heritable cancer that causes malignant immune cells to proliferate in the bone marrow. The analysis revealed two regions that may contribute to the disease: one involved in regulating DNA repair, and the other, a key gene involved in packaging DNA inside the cell's nucleus.
The myeloma findings from the new study demonstrate that high-risk pedigrees, a classic design for straightforward diseases, can also be successful for pinning down genes that contribute to complex diseases with appropriate analytics. This new strategy may be helpful for narrowing in on the genetic causes underlying other common yet complex diseases, such as obesity, diabetes and Alzheimer's disease.
Nicola Camp adds: "We are very encouraged by the new method. It certainly plays to the strengths of the large Utah pedigrees, revitalizing the family design for complex diseases. As we did in this study, the focused regions can be further investigated in smaller families to find genes and specific mutations. The method can be used for any complex disease. We are already pursuing large pedigrees in several other domains, including other cancers, psychiatric disorders, birth defects, and pre-term birth phenotypes, with several more genome-wide significant regions found. We're excited about the potential."
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Citation: Waller RG, Darlington TM, Wei X, Madsen MJ, Thomas A, Curtin K, et al. (2018) Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk. PLoS Genet 14(1): e1007111. https://doi.org/10.1371/journal.pgen.1007111
Image Credit: Rosalie G. Waller and colleagues
Image Caption: New method uses large pedigrees to narrow the search for disease causing mutations.
Funding: Research reported in this publication was supported by funding from the Utah Genome Project, (NJC); Utah Hematology Disease Oriented Team, Leukemia and Lymphoma Society, grant number 6067-09; and National Institutes of Health (NIH), grant numbers: R01-CA-107476, R01-CA-134674, R21-CA-152336, R01-CA-163353, R01-CA-167824, R01-CA-168762, R21-CA-191896, R01-DK-091374, R01-DK-093151, R01-MH-094400, R01-MH-099134, S10-OD-018522, and T15-LM-007124. Partial support for all datasets within the Utah Population Data Base is provided by the Huntsman Cancer Institute (HCI), and the HCI Cancer Center Support grant, P30-CA-42014 from the NIH. The Utah Cancer Registry is funded by the National Cancer Institute's SEER Program, Contract No. HHSN261201300017I, with additional support from the Utah Department of Health, and the University of Utah. The research reported in this publication was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001067. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
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