Dataset Information

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci.

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 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-?B 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.

SUBMITTER: Rand KA

PROVIDER: S-EPMC5524541 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci.

Rand Kristin A KA Song Chi C Dean Eric E Serie Daniel J DJ Curtin Karen K Sheng Xin X Hu Donglei D Huff Carol Ann CA Bernal-Mizrachi Leon L Tomasson Michael H MH Ailawadhi Sikander S Singhal Seema S Pawlish Karen K Peters Edward S ES Bock Cathryn H CH Stram Alex A Van Den Berg David J DJ Edlund Christopher K CK Conti David V DV Zimmerman Todd T Hwang Amie E AE Huntsman Scott S Graff John J Nooka Ajay A Kong Yinfei Y Pregja Silvana L SL Berndt Sonja I SI Blot William J WJ Carpten John J Casey Graham G Chu Lisa L Diver W Ryan WR Stevens Victoria L VL Lieber Michael R MR Goodman Phyllis J PJ Hennis Anselm J M AJ Hsing Ann W AW Mehta Jayesh J Kittles Rick A RA Kolb Suzanne S Klein Eric A EA Leske Cristina C Murphy Adam B AB Nemesure Barbara B Neslund-Dudas Christine C Strom Sara S SS Vij Ravi R Rybicki Benjamin A BA Stanford Janet L JL Signorello Lisa B LB Witte John S JS Ambrosone Christine B CB Bhatti Parveen P John Esther M EM Bernstein Leslie L Zheng Wei W Olshan Andrew F AF Hu Jennifer J JJ Ziegler Regina G RG Nyante Sarah J SJ Bandera Elisa V EV Birmann Brenda M BM Ingles Sue A SA Press Michael F MF Atanackovic Djordje D Glenn Martha J MJ Cannon-Albright Lisa A LA Jones Brandt B Tricot Guido G Martin Thomas G TG Kumar Shaji K SK Wolf Jeffrey L JL Deming Halverson Sandra L SL Rothman Nathaniel N Brooks-Wilson Angela R AR Rajkumar S Vincent SV Kolonel Laurence N LN Chanock Stephen J SJ Slager Susan L SL Severson Richard K RK Janakiraman Nalini N Terebelo Howard R HR Brown Elizabeth E EE De Roos Anneclaire J AJ Mohrbacher Ann F AF Colditz Graham A GA Giles Graham G GG Spinelli John J JJ Chiu Brian C BC Munshi Nikhil C NC Anderson Kenneth C KC Levy Joan J Zonder Jeffrey A JA Orlowski Robert Z RZ Lonial Sagar S Camp Nicola J NJ Vachon Celine M CM Ziv Elad E Stram Daniel O DO Hazelett Dennis J DJ Haiman Christopher A CA Cozen Wendy W

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20160901 12

<h4>Background</h4>Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma.<h4>Methods</h4>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 fun ...[more]

PMID: 27587788

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Project description:Genetic studies of bone mineral density (BMD) largely have been conducted in European populations. We therefore conducted a meta-analysis of six independent African ancestry cohorts to determine whether previously reported BMD loci identified in European populations were transferable to African ancestry populations. We included nearly 5000 individuals with both genetic data and assessments of BMD. Genotype imputation was conducted using the 1000G reference panel. We assessed single-nucleotide polymorphism (SNP) associations with femoral neck and lumbar spine BMD in each cohort separately, then combined results in fixed effects (or random effects if study heterogeneity was high, I2 index >60) inverse variance weighted meta-analyses. In secondary analyses, we conducted locus-based analyses of rare variants using SKAT-O. Mean age ranged from 12 to 68 years. One cohort included only men and another cohort included only women; the proportion of women in the other four cohorts ranged from 52% to 63%. Of 56 BMD loci tested, one locus, 6q25 (C6orf97, p = 8.87 × 10-4 ), was associated with lumbar spine BMD and two loci, 7q21 (SLC25A13, p = 2.84 × 10-4 ) and 7q31 (WNT16, p = 2.96 × 10-5 ), were associated with femoral neck BMD. Effects were in the same direction as previously reported in European ancestry studies and met a Bonferroni-adjusted p value threshold, the criteria for transferability to African ancestry populations. We also found associations that met locus-specific Bonferroni-adjusted p value thresholds in 11q13 (LRP5, p < 2.23 × 10-4 ), 11q14 (DCDC5, p < 5.35 × 10-5 ), and 17p13 (SMG6, p < 6.78 × 10-5 ) that were not tagged by European ancestry index SNPs. Rare single-nucleotide variants in AKAP11 (p = 2.32 × 10-2 ), MBL2 (p = 4.09 × 10-2 ), MEPE (p = 3.15 × 10-2 ), SLC25A13 (p = 3.03 × 10-2 ), STARD3NL (p = 3.35 × 10-2 ), and TNFRSF11A (p = 3.18 × 10-3 ) were also associated with BMD. The majority of known BMD loci were not transferable. Larger genetic studies of BMD in African ancestry populations will be needed to overcome limitations in statistical power and to identify both other loci that are transferable across populations and novel population-specific variants. © 2020 American Society for Bone and Mineral Research (ASBMR).

Project description:BACKGROUND/OBJECTIVES:Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition. SUBJECTS/METHODS:To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15?945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants. RESULTS:Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses. CONCLUSIONS:Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

Dataset Information

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci.

Publications

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci.

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