Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

Abstract

Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10−8), 6q21 (rs9372120, P=9.09 × 10−15), 7q36.1 (rs7781265, P=9.71 × 10−9), 8q24.21 (rs1948915, P=4.20 × 10−11), 9p21.3 (rs2811710, P=1.72 × 10−13), 10p12.1 (rs2790457, P=1.77 × 10−8), 16q23.1 (rs7193541, P=5.00 × 10−12) and 20q13.13 (rs6066835, P=1.36 × 10−13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.

Direct evidence for a polygenic etiology in familial multiple myeloma

“…As expected from the small sample size, we did not detect any variants with exome-wide significance. Looking specifically for rare variants in genes known to be associated with MM [16][17][18][19]24 (supplemental Table 3) and genes frequently somatically mutated in MM plasma cells 25,26 (supplemental Methods), we detected 10 nonsynonymous variants with minor allele frequency less than 1%. Only 2 of these were found in more than 1 case, and none of them were obviously pathogenic (supplemental Table 5).…”

“…We then extracted the genotypes of tag SNPs for the 16 risk loci that have been robustly associated with MM (supplemental Table 3) and quantified risk allele burden using 2 different scores: 1 calculated as the total number of risk alleles and 1 calculated by summarizing the number of risk alleles weighted by their log-transformed odds ratios (ORs) across all loci. For this, we used the ORs reported in Mitchell et al 18 (supplemental Table 3). To avoid statistical inflation resulting from relatedness, gene scores from individuals from the same family were averaged.…”

“…The identified risk alleles are common, have modest effects, and have been identified by comparing unselected cases with controls. Although statistical predictions suggest that they account for somewhere on the order of 20% of the familial risk, 18 no direct evidence for a polygenic etiology has been presented. It is still an open question whether familial MM is caused by aggregation of unusually high numbers of common risk alleles or by other factors (eg, rare variants with strong effects or exposure of family members to a common environmental factor).…”

“…14 Recently, genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) at 16 independent loci associated with MM risk. [16][17][18][19] Although the discovery of risk alleles proves the existence of inherited susceptibility, the genetic background of familial MM remains unclear. The identified risk alleles are common, have modest effects, and have been identified by comparing unselected cases with controls.…”

Genome-wide association study of clinical parameters in immunoglobulin light chain amyloidosis in three patient cohorts

“…Iman Meziane, 1 10 Anna Jauch, 11 Gareth J. Morgan, 3 Richard Houlston, 9,10 Hartmut Goldschmidt, 2,12 Paolo Milani, 13,14 Giampaolo Merlini, 13,14 …”