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Researchers have used high-risk pedigrees (HRPs) to identify gene variants that may cause multiple myeloma (MM).
The team’s analysis revealed shared genomic segments harboring genes with potential MM risk variants.
These single nucleotide variants (SNVs) are in USP45, a gene involved in DNA repair, and ARID1A, a gene in the SWI/SNF chromatin remodeling complex.
Nicola Camp, PhD, of the University of Utah School of Medicine in Salt Lake City, and her colleagues reported these findings in PLOS Genetics.
The researchers developed a new method to analyze HRPs (large, multi-generational families with more affected members than would be expected by chance) to identify shared regions of the genome that likely harbor MM risk variants.
The team applied the method using pedigrees from 11 Utah families at risk of MM as well as whole-exome sequencing of shared genomic segments in 1063 patients with MM or monoclonal gammopathy of undetermined significance (MGUS) and 964 control subjects.
The analysis revealed 2 regions that may contribute to MM. One was a 1.8 Mb segment at 6q16 with SNVs in USP45, and the other was a 1.2 Mb segment at 1p36.11 with SNVs in ARID1A.
One of the SNVs in USP45 was a stop gain—p.Gln691*—which was shared by 3 siblings, 1 with MM and 2 with MGUS. The other was a missense SNV—p.Gln621Glu—which was shared by 2 of 4 siblings in a family, 1 with MM and 1 with MGUS.
One of the missense SNVs in ARID1A—rs752026201, p. Ser90Gly—was shared by 3 MM cases. The other missense SNV—rs140664170, p.Met890Val—was shared by 2 cousins with MM.
The researchers believe these findings show that HRPs can be effective for identifying risk variants in complex diseases.
“We are very encouraged by the new method,” Dr Camp said. “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.” 
Researchers have used high-risk pedigrees (HRPs) to identify gene variants that may cause multiple myeloma (MM).
The team’s analysis revealed shared genomic segments harboring genes with potential MM risk variants.
These single nucleotide variants (SNVs) are in USP45, a gene involved in DNA repair, and ARID1A, a gene in the SWI/SNF chromatin remodeling complex.
Nicola Camp, PhD, of the University of Utah School of Medicine in Salt Lake City, and her colleagues reported these findings in PLOS Genetics.
The researchers developed a new method to analyze HRPs (large, multi-generational families with more affected members than would be expected by chance) to identify shared regions of the genome that likely harbor MM risk variants.
The team applied the method using pedigrees from 11 Utah families at risk of MM as well as whole-exome sequencing of shared genomic segments in 1063 patients with MM or monoclonal gammopathy of undetermined significance (MGUS) and 964 control subjects.
The analysis revealed 2 regions that may contribute to MM. One was a 1.8 Mb segment at 6q16 with SNVs in USP45, and the other was a 1.2 Mb segment at 1p36.11 with SNVs in ARID1A.
One of the SNVs in USP45 was a stop gain—p.Gln691*—which was shared by 3 siblings, 1 with MM and 2 with MGUS. The other was a missense SNV—p.Gln621Glu—which was shared by 2 of 4 siblings in a family, 1 with MM and 1 with MGUS.
One of the missense SNVs in ARID1A—rs752026201, p. Ser90Gly—was shared by 3 MM cases. The other missense SNV—rs140664170, p.Met890Val—was shared by 2 cousins with MM.
The researchers believe these findings show that HRPs can be effective for identifying risk variants in complex diseases.
“We are very encouraged by the new method,” Dr Camp said. “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.”
Researchers have used high-risk pedigrees (HRPs) to identify gene variants that may cause multiple myeloma (MM).
The team’s analysis revealed shared genomic segments harboring genes with potential MM risk variants.
These single nucleotide variants (SNVs) are in USP45, a gene involved in DNA repair, and ARID1A, a gene in the SWI/SNF chromatin remodeling complex.
Nicola Camp, PhD, of the University of Utah School of Medicine in Salt Lake City, and her colleagues reported these findings in PLOS Genetics.
The researchers developed a new method to analyze HRPs (large, multi-generational families with more affected members than would be expected by chance) to identify shared regions of the genome that likely harbor MM risk variants.
The team applied the method using pedigrees from 11 Utah families at risk of MM as well as whole-exome sequencing of shared genomic segments in 1063 patients with MM or monoclonal gammopathy of undetermined significance (MGUS) and 964 control subjects.
The analysis revealed 2 regions that may contribute to MM. One was a 1.8 Mb segment at 6q16 with SNVs in USP45, and the other was a 1.2 Mb segment at 1p36.11 with SNVs in ARID1A.
One of the SNVs in USP45 was a stop gain—p.Gln691*—which was shared by 3 siblings, 1 with MM and 2 with MGUS. The other was a missense SNV—p.Gln621Glu—which was shared by 2 of 4 siblings in a family, 1 with MM and 1 with MGUS.
One of the missense SNVs in ARID1A—rs752026201, p. Ser90Gly—was shared by 3 MM cases. The other missense SNV—rs140664170, p.Met890Val—was shared by 2 cousins with MM.
The researchers believe these findings show that HRPs can be effective for identifying risk variants in complex diseases.
“We are very encouraged by the new method,” Dr Camp said. “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.”