A Meta-Analysis Of Genome-Wide Association Studies Of Multiple Myeloma In Cases and Controls Of European Origin Identifies a Risk Locus In 12q23.1
Authors: Rand Kristin A , Camp Nicola , Martino Alessandro , Dean Eric W. , Serie Daniel J. , Edlund Christopher K. , Hu Donglei , Curtin Karen , Huntsman Scott , Van Den Berg David J. , De Roos Anneclaire , Brown Elizabeth E , Giles Graham G. , Spinelli John J. , Ailawadhi Sikander , Birmann Brenda M. , Brooks-Wilson Angela R , Severson Richard K , Bracci Paige M , Gebregziabher Mulugeta , Tomasson Michael H. , Mohrbacher Ann M. , Tricot Guido J. , Campa Daniele , Martin Thomas , Henderson Brian E. , Zangari Maurizio , Rothman Nathaniel , Chanock Stephen Jacob , Kumar Shaji , Kolonel Laurence N. , Lee Wolf Jeffrey , Colditz Graham A , Rajkumar S. Vincent , Munshi Nikhil C. , Anderson Kenneth C. , Haiman Christopher , Conti David V. , Canzian Federico , Vachon Celine M , Ziv Elad , Cozen Wendy 
Published: October 2019

Abstract

Introduction
The 2-3 fold excess risk of multiple myeloma (MM) among family members of cases suggests a heritable contribution to risk. Recently, a genome-wide association study (GWAS) identified two genome-wide significant and one promising novel loci associated with multiple myeloma risk. To confirm these associations and identify additional novel risk loci, we performed a four-center, genome-wide association meta-analysis.

Methods
A fixed effects model was used for the meta-analysis which included a total of 1248 cases and 1485 controls, all of European descent, genotyped and analyzed at four separate centers with samples contributed by 10 studies. After quality control and imputation using the 1000 Genomes Project, the analysis included ∼9.5 million variants (λ=1.024). Associations between (single nucleotide polymorphisms) SNP genotypes and MM risk were evaluated under a log-additive model of inheritance, with each study adjusting for age, sex, and up to 10 principal components to control for population stratification. Promising results were replicated in an independent set of 1587 cases and 1770 controls using TaqMan, for a total of 2835 and 3255 cases and controls, respectively, in a combined meta-analysis.

Results
The discovery meta-analysis did not reveal any genome-wide significant associations (defined as p<5 x 10-8). We used a novel pruning algorithm to identify the top 35 most promising single nucleotide polymorphisms (SNPs) to advance to replication. We successfully genotyped 22 SNPs in the replication set. In the combined discovery and replication meta-analysis, rs1345359 at 12q23.1 was the most strongly associated SNP (P=9 x 10-8, Table 1). The variant allele C was associated with reduced risk (odds ratio discovery set [OR]= 0.69, OR replication set = 0.78, OR combined = 0.74). A second locus at 20q13.2 (rs150220835), was associated with a two-fold increased risk (P=1.22 x 10-6), a borderline increased risk (P=0.0900) and 45% increased risk (P=2.44 X 10-5) in the discovery, replication, and combined analysis sets respectively (Table 1).
We also confirmed the association between MM risk and two previously published SNPs (rs4487645, p=0.0007and rs105251, p=0.0044) (Broderick et al., Nat. Genet., 2011). The third previously suggested SNP (rs6746082) was of nominal significance (p=0.0517) in the meta-analysis.

Discussion
We confirmed the association between MM risk and two previously published SNPs and identified a possible association with a novel SNP in chromosome 12q23.1 (rs1345359). This SNP is not located in a gene nor associated with biofeatures in ENCODE, thus further examination of correlated SNPs is necessary to identify a functional SNP linked to this locus. We also found suggestive evidence for a second locus at 20q13.2 requiring additional replication. Larger studies would improve risk variant discovery for this rare hematologic malignancy.

Disclosures:
Wolf: Celgene: Honoraria, Research Funding; Millenium: Honoraria; Onyx: Honoraria. Anderson:Celgene, Millennium, BMS, Onyx: Membership on an entity’s Board of Directors or advisory committees; Acetylon, Oncopep: Scientific Founder , Scientific Founder Other.