A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry
Du Z, Weinhold N, Song GC, Rand KA, Van Den Berg DJ, Hwang AE, Sheng X, Hom V, Ailawadhi S, Nooka AK, Singhal S, Pawlish K, Peters ES, Bock C, Mohrbacher A, Stram A, Berndt SI, Blot WJ, Casey G, Stevens VL, Kittles R, Goodman PJ, Diver WR, Hennis A, Nemesure B, Klein EA, Rybicki BA, Stanford JL, Witte JS, Signorello L, John EM, Bernstein L, Stroup AM, Stephens OW, Zangari M, Van Rhee F, Olshan A, Zheng W, Hu JJ, Ziegler R, Nyante SJ, Ingles SA, Press MF, Carpten JD, Chanock SJ, Mehta J, Colditz GA, Wolf J, Martin TG, Tomasson M, Fiala MA, Terebelo H, Janakiraman N, Kolonel L, Anderson KC, Le Marchand L, Auclair D, Chiu BC, Ziv E, Stram D, Vij R, Bernal-Mizrachi L, Morgan GJ, Zonder JA, Huff CA, Lonial S, Orlowski RZ, Conti DV, Haiman CA, and Cozen W. A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry. Blood Adv 2020; 4(1):181-190.
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.