A Meta-Analysis of Genome-Wide Association Studies of Multiple Myeloma in Persons of African Ancestry [African-American Multiple Myeloma Study (AAMMS)] Identifies Suggestive Risk Variants

Background: Multiple myeloma (MM) is 2-3 times more common among persons of African ancestry (AA) compared to those of European ancestry (EA). The 2-3-fold increased risk among family members of cases suggests a genetic contribution to risk. Genome-wide association studies (GWAS) in EA populations have identified 16 novel risk loci. We previously showed that 5 of these replicated in populations of AA (Rand et al., CEBP, 2016). In order to increase the power to identify additional novel common genetic risk variants, we conducted a GWAS meta-analysis using two sets of AA MM patients recruited into the African American Multiple Myeloma Study (AAMMS) and the University of Arkansas for Medical Sciences (UAMS)) Myeloma Institute.

Methods: The first GWAS included 1,305 incident AA MM cases enrolled in AAMMS, recruited from 10 clinical centers and population-based cancer registries in the NCI SEER Program from 2011 to 2013 and genotyped using the Illumina HumanCore GWAS array. Control data were obtained from 4425 male controls from the African Ancestry Prostate Cancer Consortium (consisting of 14 independent studies) and 2632 female controls from a breast cancer GWAS of African-American women (consisting of 9 independent studies) and genotyped using the Illumina 1M-Duo. The second GWAS included 95 additional AAMMS patients and 435 AA MM patients enrolled from UAMS, genotyped using the Illumina MegaBead Chip and compared to 2,390 AA controls from the Multiethnic Cohort. Both GWAS were imputed with the CAAPA Haplotype Reference panel on the University of Michigan Imputation Server http://www.caapa-project.org/. Single nucleotide polymorphisms (SNPs) with a minor allele frequency of less than 0.01 and an imputation score of less than 0.8 were excluded. Associations between SNPs and MM risk in each GWAS were calculated using unconditional logistic regression adjusted for sex, age at diagnosis (cases) or cohort sample collection (controls), and the first 10 genetic ancestry principal components. A meta-analysis of the two GWAS was conducted using a fixed effects model.

Results: There were 8,715,278 overlapping SNPs in the meta-analysis with a lambda (inflation) = 1.066. Seven loci were associated with MM risk at p<10^-6, but none reached genome-wide significance. We found several novel SNPs at the previously reported locus 6p21.33, with odds ratios (ORs) ranging from 1.20-1.28 and p-values ranging from 3.72-8.46 x 10^-7 (Figure 1). We also identified six additional suggestive novel loci at chr4q32.1, chr9p24.3, chr12q12, chr12p13.3, chr16p12.2, chr18q12.1 with ORs ranging from 1.27-2.13 and p-values from 1.2x10^-7-9.39x10^-7.

Of the 16 known risk loci in EA MM patients, eight replicated at p<0.05 in the AA MM GWAS meta-analysis. We previously reported better localized signals in AA patients for 7 of these known risk SNPs; five of these replicated at p< 0.05 in this meta-analysis. The highest p-value for the previously identified EA or AA SNPs was 1.90 x10^-5.

Conclusions: We have found suggestive loci associated with MM risk in AA's that appear distinct from risk loci identified in EA's, that may explain some of the disparity for MM risk in these two populations. Further follow-up with replication is warranted.

Figure 1. A Manhattan plot showing results of a fixed effects meta-analysis of two genome wide association scans based on a total of 1,835 multiple myeloma patients and 9,468 controls of African ancestry, with genome-wide significance of p= 5x10^-8 (red line). Y-axis= -Log10 of the p-value; X-axis= chromosomes; green dots= previously reported risk loci, excluding those with imputation scores<0.8 and a minor allele frequency of <1%.

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