Multiple myeloma has historically not been considered an “inheritable” disease. But myeloma researchers at the University of Utah and others have found that two familial gene regions could contribute to the development of multiple myeloma. They shared their findings in a recent paper in PLOS Genetics.
Tracking the DNA of family histories can help geneticists track disease through different branches of a family tree to pinpoint responsible mutations. This process is straightforward in diseases caused by a mutation in a single gene, but for complex diseases which involve multiple genes, the method has not been as effective.
In the study, researchers developed a new method called the Shared Genomic Segment (SGS) 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 and 1063 myeloma or MGUS patients. Utah has some of the largest family DNA collections in the world, thanks in part to services like Ancestry.com and the Utah Genome project.
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.
Exome sequencing in the 6a16 region showed a mutated gene called USP45, known to influence DNA repair. Also, a segment at 1p36.11 was found in two of the Utah families with genetic code changes in ARID1A, a key gene for the SWI/SNF chromatin remodeling complex, a group of proteins that remodel the way DNA is packaged.
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.
Study author Nicola Camp says:
“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.”