Year: 2021
Type: article
Study design: Observational Study
Abstract: Inherited genetic risk factors play a role in multiple myeloma (MM), yet considerable missing heritability exists. Rare risk variants at genome-wide association study (GWAS) loci are a new avenue to explore. Pleiotropy between lymphoid neoplasms (LNs) has been suggested in family history and genetic studies, but no studies have interrogated sequencing for pleiotropic genes or rare risk variants. Sequencing genetically enriched cases can help discover rarer variants. We analyzed exome sequencing in familial or early-onset MM cases to identify rare, functionally relevant variants near GWAS loci for a range of LNs. A total of 149 distinct and significant LN GWAS loci have been published. We identified six recurrent, rare, potentially deleterious variants within 5 kb of significant GWAS single nucleotide polymorphisms in 75 MM cases. Mutations were observed in BTNL2, EOMES, TNFRSF13B, IRF8, ACOXL and TSPAN32. All six genes replicated in an independent set of 255 early-onset MM or familial MM or precursor cases. Expansion of our analyses to the full length of these six genes resulted in a list of 39 rare and deleterious variants, seven of which segregated in MM families. Three genes also had significant rare variant burden in 733 sporadic MM cases compared with 935 control individuals: IRF8 (P = 1.0 × 10-6), EOMES (P = 6.0 × 10-6) and BTNL2 (P = 2.1 × 10-3). Together, our results implicate six genes in MM risk, provide support for genetic pleiotropy between LN subtypes and demonstrate the utility of sequencing genetically enriched cases to identify functionally relevant variants near GWAS loci.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddab066
Institutions: University of Utah, Icahn School of Medicine at Mount Sinai, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, Centre international de recherche sur le cancer, Mayo Clinic, University of South Carolina, Huntsman Cancer Institute, Centre National de la Recherche Scientifique, Inserm, Centre de Recherche en Cancérologie de Lyon
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,922
Funders: World Health Organization, Huntsman Cancer Foundation, Huntsman Cancer Institute, Institut National Du Cancer, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1019374866, Comprehensive Sequencing and Analysis of Variation in NHLBI Cohorts, G1261793039, MESA, G1276754516, G1338205306, G1409423729, G140944187, G1640378483, G1686417863, Genetics of Common Cancers: Discovery to Implementation, Whole Genome Sequencing to Discover Familial Myeloma Risk Genes, G2032172404, G2144938473, G22458031, G2262782284, Northwest Genomics Center, MESA, Institute for Clinical and Translational Research (UL1), ARRA - NHLBI Lung Cohorts Sequencing Project, MESA, G2837638605, G290884426, G291913881, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, G2995161194, G3351322984, G3550174423, G3581052147, G3647016462, G3667269547, G3687594596, MESA, G399481048, Big Omics Data Engine 2 Supercomputer, TITLE: MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), G4401650913, G4512137732, G475171617, OPTION 3. 4/1/2014 - 3/31/2015. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) - READING CENTER, NHLBI, MESA, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY-ULTRASOUND, Genetics of Common Cancers: Discovery to Implementation, G5787256936, G5848925640, G6095866717, G6220138500, G6359107525, MESA, G6514094751, Human Exome Sequencing in Six Well-Phenotyped NHLBI Cohorts, G66341962, WHI Sequencing Project (WHISP), MESA, G78770644, Candidate Gene Resequencing of Germline Multiple Myeloma, G805458286, Clinical and Translational Science Award, G843766559, G8852914737, Cancer Center Support Grant, Cancer Center Support Grant, G991334795
OpenAlex ID: W3135320242