Abstract PR05: A meta-analysis of genome-wide association study and eQTL analysis of multiple myeloma among African Americans
Authors: Du Zhaohui , Weinhold Niels , Song Gregory Chi , Rand Kristen A. , Van Den Berg David J. , Hwang Amie E. , Sheng Xin , Hom Victor , Ailawadhi Sikander , Nooka Ajay K. , Singhal Seema , Pawlish Karen , Peters Edward , Bock Cathryn , Mohrbacher Ann , Stram Alexander , Berndt Sonja I. , Blot William J. , Casey Graham , Stevens Victoria L. , Kittles Rick , Goodman Phyllis J. , Diver W. Ryan , Hennis Anselm , Nemesure Barbara , Klein Eric A. , Rybicki Benjamin A. , Stanford Janet L. , Witte John S. , Signorello Lisa , John Esther M. , Bernstein Leslie , Stroup Antoinette , Stephens Owen W. , Zangari Maurizio , Van Rhee Frits , Olshan Andrew , Zheng Wei , Hu Jennifer J. , Ziegler Regina , Nyante Sarah J. , Ingles Sue Ann , Press Michael , Carpten John David , Chanock Stephen , Mehta Jayesh , Colditz Graham A , Wolf Jeffrey , Martin Thomas G. , Tomasson Michael , Fiala Mark A. , Terebelo Howard , Janakiraman Nalini , Kolonel Laurence , Anderson Kenneth C. , Le Marchand Loic , Auclair Daniel , Chiu Brian C.-H. , Ziv Elad , Stram Daniel , Vij Ravi , Bernal-Mizrachi Leon , Morgan Gareth J. , Zonder Jeffrey A. , Huff Carol Ann , Lonial Sagar , Orlowski Robert Z. , Conti David V. , Haiman Christopher A. , Cozen Wendy 
Published: September 2020

Background: Persons of African ancestry (AA) experience a 1.5-2-fold risk of multiple myeloma (MM) compared to persons of European ancestry (EA). We assembled a set of MM patients with self-reported AA in order to evaluate the contribution of genetics to etiology in this high-risk group.

Methods: Here we present the results of a meta-analysis of two GWAS in 1,813 cases and 8,871 controls of AA. We also conducted an admixture mapping scan to identify risk alleles associated with local ancestry, 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. Finally, we conducted an eQTL analysis measuring gene expression in those genes harboring a risk variant in malignant plasma cells from 292 of the patients from a single site.

Results: In GWAS analysis, we identified two suggestive novel loci located at 9p24.3 and 9p13.1 at P&lt;1 × 10-6, but 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. 20 of the 23 known EA risk variants showed directional consistency and 9 replicated at P&lt;0.05 in AA individuals. In eight regions, we identified markers that better capture MM risk in persons of AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95%CI: 1.56, 2.11) increased MM risk compared to 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).

Conclusion: Our study shows that common genetic variation contributes to MM risk individuals of AA.

This abstract is also being presented as Poster C040.

Citation Format: Zhaohui Du, Niels Weinhold, Gregory Chi Song, Kristen A. Rand, David J. Van Den Berg, Amie E. Hwang, Xin Sheng, Victor Hom, Sikander Ailawadhi, Ajay K. Nooka, Seema Singhal, Karen Pawlish, Edward Peters, Cathryn Bock, Ann Mohrbacher, Alexander Stram, Sonja I. Berndt, William J. Blot, Graham Casey, Victoria L. Stevens, Rick Kittles, Phyllis J. Goodman, W. Ryan Diver, Anselm Hennis, Barbara Nemesure, Eric A. Klein, Benjamin A. Rybicki, Janet L. Stanford, John S. Witte, Lisa Signorello, Esther M. John, Leslie Bernstein, Antoinette Stroup, Owen W. Stephens, Maurizio Zangari, Frits Van Rhee, Andrew Olshan, Wei Zheng, Jennifer J. Hu, Regina Ziegler, Sarah J. Nyante, Sue Ann Ingles, Michael Press, John David Carpten, Stephen Chanock, Jayesh Mehta, Graham A Colditz, Jeffrey Wolf, Thomas G. Martin, Michael Tomasson, Mark A. Fiala, Howard Terebelo, Nalini Janakiraman, Laurence Kolonel, Kenneth C. Anderson, Loic Le Marchand, Daniel Auclair, Brian C.-H. Chiu, Elad Ziv, Daniel Stram, Ravi Vij, Leon Bernal-Mizrachi, Gareth J. Morgan, Jeffrey A. Zonder, Carol Ann Huff, Sagar Lonial, Robert Z. Orlowski, David V. Conti, Christopher A. Haiman, Wendy Cozen. A meta-analysis of genome-wide association study and eQTL analysis of multiple myeloma among African Americans [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR05.