A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry

Zhaohui Du, Niels Weinhold, Gregory Chi Song, Kristin A. Rand, David J. Van Den Berg, Amie E. Hwang, Xin Sheng, Victor Hom, Sikander Ailawadhi, Ajay K. Nooka, Seema Singhal, Karen Pawlish, Edward S. Peters, Cathryn Bock, Ann Mohrbacher, Alexander Stram, Sonja I. Berndt, William J. Blot, Graham Casey, Victoria L. StevensRick Kittles, Phyllis J. Goodman, W. Ryan Diver, Anselm Hennis, Barbara Nemesure, Eric A. Klein, Benjamin A. Rybicki, Janet L. Stanford, John S. Witte, Lisa Signorello, Esther M. John, Leslie Bernstein, Antoinette M. Stroup, Owen W. Stephens, Maurizio Zangari, Frits Van Rhee, Andrew Olshan, Wei Zheng, Jennifer J. Hu, Regina Ziegler, Sarah J. Nyante, Sue Ann Ingles, Michael F. Press, John David Carpten, Stephen J. Chanock, Jayesh Mehta, Graham A. Colditz, Jeffrey Wolf, Thomas G. Martin, Michael Tomasson, Mark A. Fiala, Howard Terebelo, Nalini Janakiraman, Laurence Kolonel, Kenneth C. Anderson, Loic Le Marchand, Daniel Auclair, Brian C.H. Chiu, Elad Ziv, Daniel Stram, Ravi Vij, Leon Bernal-Mizrachi, Gareth J. Morgan, Jeffrey A. Zonder, Carol Ann Huff, Sagar Lonial, Robert Z. Orlowski, David V. Conti, Christopher A. Haiman, Wendy Cozen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs ofMMin 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better captureMMrisk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

Original languageEnglish (US)
Pages (from-to)181-190
Number of pages10
JournalBlood Advances
Volume4
Issue number1
DOIs
StatePublished - Jan 14 2020

Funding

CA092447 (L.S.). The collection of incident MM patients used in this study was supported by the California Department of Health Services as part of the statewide cancer-reporting program mandated by California Health and Safety Code Section 103885 and by a grant from the Centers for Disease Control and Prevention to support cancer patient registration and ascertainment (1U58DP000807-01). Patient identification was made possible by federal funds from the NCI Surveillance Epidemiology and End Results Population-based Registry Program, NIH, Department of Health and Human Services. Genotyping of cases and some controls was performed at the University of Southern California Norris Comprehensive Cancer Center Genomics Core, which is supported by NCI Comprehensive Cancer Center Core grant P30 CA014089. Patient accrual and sample processing at Johns Hopkins Medical Center was supported by the NCI Sidney Kimmel Comprehensive Cancer Center core grant P30 CA006973. Conflict-of-interest disclosure: C. A. Huff has acted as a consultant for Karyopharm Therapeutics, Sanofi, and miDiagnostics and is a member of the Safety Monitoring Board for Johnson and Johnson. T.G.M. has acted as a consultant for Roche and Juno Therapeutics and has received research funding from Amgen, Sanofi, and Seattle Genetics. J.M. is a member of the Speakers Bureau for Takeda Pharma-cauticals and Celgene and owns stock in Celgene, Bristol-Myers The work was supported by NCI, National Institutes of Health (NIH) grants 1R01CA134786 (W.C. and C. A. Haiman), R01 CA84979 (S.A.I.), 5U01CA164973 (L.L.M. and C. A. Haiman), P30CA01409 and P50CA100707 (K.C.A.), R21 CA1918896 (E.Z.), and R01

ASJC Scopus subject areas

  • Hematology

Fingerprint

Dive into the research topics of 'A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry'. Together they form a unique fingerprint.

Cite this