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

Author:

Du Zhaohui1ORCID,Weinhold Niels2,Song Gregory Chi3,Rand Kristin A.3,Van Den Berg David J.1,Hwang Amie E.3ORCID,Sheng Xin1ORCID,Hom Victor3,Ailawadhi Sikander4,Nooka Ajay K.5,Singhal Seema6,Pawlish Karen7,Peters Edward S.8ORCID,Bock Cathryn9ORCID,Mohrbacher Ann10,Stram Alexander3ORCID,Berndt Sonja I.11,Blot William J.12,Casey Graham13,Stevens Victoria L.14,Kittles Rick15,Goodman Phyllis J.16,Diver W. Ryan14ORCID,Hennis Anselm17,Nemesure Barbara17,Klein Eric A.18,Rybicki Benjamin A.19,Stanford Janet L.20,Witte John S.21,Signorello Lisa11,John Esther M.22ORCID,Bernstein Leslie15,Stroup Antoinette M.723ORCID,Stephens Owen W.2,Zangari Maurizio2,Van Rhee Frits2,Olshan Andrew24,Zheng Wei12,Hu Jennifer J.25,Ziegler Regina11ORCID,Nyante Sarah J.26,Ingles Sue Ann3,Press Michael F.27,Carpten John David28,Chanock Stephen J.11,Mehta Jayesh6,Colditz Graham A.29ORCID,Wolf Jeffrey21,Martin Thomas G.21,Tomasson Michael30,Fiala Mark A.29,Terebelo Howard31ORCID,Janakiraman Nalini32,Kolonel Laurence33,Anderson Kenneth C.34,Le Marchand Loic33,Auclair Daniel35ORCID,Chiu Brian C.-H.36,Ziv Elad21,Stram Daniel3ORCID,Vij Ravi29,Bernal-Mizrachi Leon37,Morgan Gareth J.38,Zonder Jeffrey A.9,Huff Carol Ann39,Lonial Sagar5,Orlowski Robert Z.40,Conti David V.1,Haiman Christopher A.1,Cozen Wendy127ORCID

Affiliation:

1. Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA;

2. Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR;

3. Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA;

4. Division of Hematology-Oncology, Mayo Clinic, Jacksonville, FL;

5. Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University, Atlanta, GA;

6. Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL;

7. Cancer Epidemiology Services, Epidemiology, Environmental and Occupational Health Division, New Jersey Department of Health, Trenton, NJ;

8. Department of Epidemiology, Louisiana State University School of Public Health, New Orleans, LA;

9. Karmanos Cancer Center, Wayne State University, Detroit, MI;

10. Division of Hematology, Department of Medicine, University of Southern California, Los Angeles, CA;

11. Division of Cancer Genetics and Epidemiology, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD;

12. Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN;

13. Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA;

14. American Cancer Society, Atlanta, GA;

15. City of Hope National Medical Center, Duarte, CA;

16. The Southwest Oncology Group Statistical Center, Seattle, WA;

17. Department of Preventive Medicine, Stony Brook University, Stony Brook, NY;

18. Cleveland Clinic Foundation, Cleveland, OH;

19. Henry Ford Hospital, Detroit, MI;

20. Fred Hutchinson Cancer Center, Seattle, WA;

21. Department of Epidemiology and Biostatistics, University of California, San Francisco, CA;

22. Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA;

23. Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Rutgers University, New Brunswick, NJ;

24. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC;

25. Department of Public Health Sciences, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL;

26. Department of Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC;

27. Department of Pathology, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA;

28. Center for Translational Genomics, Department of Translational Genomics, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA;

29. Division of Oncology, Washington University School of Medicine, Saint Louis, MO;

30. Division of Hematology, Oncology and Bone Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA;

31. Providence Hospital, Southfield, MI;

32. Division of Hematology-Oncology, Henry Ford Hospital, Detroit, MI;

33. University of Hawaii Cancer Center, Honolulu, HI;

34. J. Lipper Cancer Center for Multiple Myeloma, Dana-Farber Cancer Institute, Harvard University, Boston, MA;

35. Multiple Myeloma Research Foundation, Norwalk, CT;

36. Department of Public Health Sciences, University of Chicago, Chicago, IL;

37. Grady Memorial Hospital, Emory University, Atlanta, GA;

38. Myeloma Center, Perlmutter Cancer Center, New York University, New York, NY;

39. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD; and

40. Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX

Abstract

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 of MM in 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 capture MM risk 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.

Publisher

American Society of Hematology

Subject

Hematology

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