Dataset Information

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

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.

SUBMITTER: Du Z

PROVIDER: S-EPMC6960456 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Du Zhaohui Z Weinhold Niels N Song Gregory Chi GC Rand Kristin A KA Van Den Berg David J DJ Hwang Amie E AE Sheng Xin X Hom Victor V Ailawadhi Sikander S Nooka Ajay K AK Singhal Seema S Pawlish Karen K Peters Edward S ES Bock Cathryn C Mohrbacher Ann A Stram Alexander A Berndt Sonja I SI Blot William J WJ Casey Graham G Stevens Victoria L VL Kittles Rick R Goodman Phyllis J PJ Diver W Ryan WR Hennis Anselm A Nemesure Barbara B Klein Eric A EA Rybicki Benjamin A BA Stanford Janet L JL Witte John S JS Signorello Lisa L John Esther M EM Bernstein Leslie L Stroup Antoinette M AM Stephens Owen W OW Zangari Maurizio M Van Rhee Frits F Olshan Andrew A Zheng Wei W Hu Jennifer J JJ Ziegler Regina R Nyante Sarah J SJ Ingles Sue Ann SA Press Michael F MF Carpten John David JD Chanock Stephen J SJ Mehta Jayesh J Colditz Graham A GA Wolf Jeffrey J Martin Thomas G TG Tomasson Michael M Fiala Mark A MA Terebelo Howard H Janakiraman Nalini N Kolonel Laurence L Anderson Kenneth C KC Le Marchand Loic L Auclair Daniel D Chiu Brian C-H BC Ziv Elad E Stram Daniel D Vij Ravi R Bernal-Mizrachi Leon L Morgan Gareth J GJ Zonder Jeffrey A JA Huff Carol Ann CA Lonial Sagar S Orlowski Robert Z RZ Conti David V DV Haiman Christopher A CA Cozen Wendy W

Blood advances 20200101 1

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 susceptibilit ...[more]

PMID: 31935283

Similar Datasets

Project description:Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ? 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure