A meta-analysis of multiple myeloma risk regions in African and European ancestry populations identifies putatively functional loci

Kristin A. Rand, Chi Song, Eric Dean, Daniel J. Serie, Karen Curtin, Xin Sheng, Donglei Hu, Carol Ann Huff, Leon Bernal-Mizrachi, H. Michael Tomasson, Sikander Ailawadhi, Seema Singhal, Karen Pawlish, Edward S. Peters, Cathryn H. Bock, Alex Stram, David J. Van Den Berg, Christopher K. Edlund, David V. Conti, Todd ZimmermanAmie E. Hwang, Scott Huntsman, John Graff, Ajay Nooka, Yinfei Kong, Silvana L. Pregja, Sonja I. Berndt, William J. Blot, John Carpten, Graham Casey, Lisa Chu, W. Ryan Diver, Victoria L. Stevens, Michael R. Lieber, Phyllis J. Goodman, Anselm J.M. Hennis, Ann W. Hsing, Jayesh Mehta, Rick A. Kittles, Suzanne Kolb, Eric A. Klein, Cristina Leske, Adam B. Murphy, Barbara Nemesure, Christine Neslund-Dudas, Sara S. Strom, Ravi Vij, Benjamin A. Rybicki, Janet L. Stanford, Lisa B. Signorello, John S. Witte, Christine B. Ambrosone, Parveen Bhatti, Esther M. John, Leslie Bernstein, Wei Zheng, Andrew F. Olshan, Jennifer J. Hu, Regina G. Ziegler, Sarah J. Nyante, Elisa V. Bandera, Brenda M. Birmann, Sue A. Ingles, Michael F. Press, Djordje Atanackovic, Martha J. Glenn, Lisa A. Cannon-Albright, Brandt Jones, Guido Tricot, Thomas G. Martin, Shaji K. Kumar, Jeffrey L. Wolf, Sandra L. Deming Halverson, Nathaniel Rothman, Angela R. Brooks-Wilson, S. Vincent Rajkumar, Laurence N. Kolonel, Stephen J. Chanock, Susan L. Slager, Richard K. Severson, Nalini Janakiraman, Howard R. Terebelo, Elizabeth E. Brown, Anneclaire J. De Roos, Ann F. Mohrbacher, Graham A. Colditz, Graham G. Giles, John J. Spinelli, Brian C. Chiu, Nikhil C. Munshi, Kenneth C. Anderson, Joan Levy, Jeffrey A. Zonder, Robert Z. Orlowski, Sagar Lonial, Nicola J. Camp, Celine M. Vachon, Elad Ziv, Daniel O. Stram, Dennis J. Hazelett, Christopher A. Haiman, Wendy Cozen

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry- European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 30 end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10-7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-kB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional.

Original languageEnglish (US)
Pages (from-to)1609-1618
Number of pages10
JournalCancer Epidemiology Biomarkers and Prevention
Volume25
Issue number12
DOIs
StatePublished - Dec 1 2016

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ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Rand, K. A., Song, C., Dean, E., Serie, D. J., Curtin, K., Sheng, X., Hu, D., Huff, C. A., Bernal-Mizrachi, L., Tomasson, H. M., Ailawadhi, S., Singhal, S., Pawlish, K., Peters, E. S., Bock, C. H., Stram, A., Van Den Berg, D. J., Edlund, C. K., Conti, D. V., ... Cozen, W. (2016). A meta-analysis of multiple myeloma risk regions in African and European ancestry populations identifies putatively functional loci. Cancer Epidemiology Biomarkers and Prevention, 25(12), 1609-1618. https://doi.org/10.1158/1055-9965.EPI-15-1193