A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci
Authors: Rand Kristin A. , Song Chi , Dean Eric , Serie Daniel J. , Curtin Karen , Sheng Xin , Hu Donglei , Huff Carol Ann , Bernal-Mizrachi Leon , Tomasson Michael H. , Ailawadhi Sikander , Singhal Seema , Pawlish Karen , Peters Edward S. , Bock Cathryn H. , Stram Alex , Van Den Berg David J. , Edlund Christopher K. , Conti David V. , Zimmerman Todd , Hwang Amie E. , Huntsman Scott , Graff John , Nooka Ajay , Kong Yinfei , Pregja Silvana L. , Berndt Sonja I. , Blot William J. , Carpten John , Casey Graham , Chu Lisa , Diver W. Ryan , Stevens Victoria L. , Lieber Michael R. , Goodman Phyllis J. , Hennis Anselm J.M. , Hsing Ann W. , Mehta Jayesh , Kittles Rick A. , Kolb Suzanne , Klein Eric A. , Leske Cristina , Murphy Adam B. , Nemesure Barbara , Neslund-Dudas Christine , Strom Sara S. , Vij Ravi , Rybicki Benjamin A. , Stanford Janet L. , Signorello Lisa B. , Witte John S. , Ambrosone Christine B. , Bhatti Parveen , John Esther M. , Bernstein Leslie , Zheng Wei , Olshan Andrew F. , Hu Jennifer J. , Ziegler Regina G. , Nyante Sarah J. , Bandera Elisa V. , Birmann Brenda M. , Ingles Sue A. , Press Michael F. , Atanackovic Djordje , Glenn Martha J. , Cannon-Albright Lisa A. , Jones Brandt , Tricot Guido , Martin Thomas G. , Kumar Shaji K. , Wolf Jeffrey L. , Deming Halverson Sandra L. , Rothman Nathaniel , Brooks-Wilson Angela R. , Rajkumar S. Vincent , Kolonel Laurence N. , Chanock Stephen J. , Slager Susan L. , Severson Richard K. , Janakiraman Nalini , Terebelo Howard R. , Brown Elizabeth E. , De Roos Anneclaire J. , Mohrbacher Ann F. , Colditz Graham A. , Giles Graham G. , Spinelli John J. , Chiu Brian C. , Munshi Nikhil C. , Anderson Kenneth C. , Levy Joan , Zonder Jeffrey A. , Orlowski Robert Z. , Lonial Sagar , Camp Nicola J. , Vachon Celine M. , Ziv Elad , Stram Daniel O. , Hazelett Dennis J. , Haiman Christopher A. , Cozen Wendy 
Published: September 2016

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 &lt; 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 3′ 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-κB 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. Cancer Epidemiol Biomarkers Prev; 25(12); 1609–18. ©2016 AACR.