Regions on Chromosomes 1 and 14 Are Associated with VWF:Ag Levels in African Americans Using Mapping By Admixture Linkage Disequilibrium

Abstract Background: VWF:Ag is highly heritable, however, despite genome-wide linkage and association analysis, mostly in European derived populations, the genetic basis for VWF levels is only partially understood. African Americans (AfAm) have significantly higher VWF:Ag than European Americans: although variants in VWF and ABO can account for some of this, it is not clear whether they explain all of this ethnic difference. A powerful method to identify chromosomal regions that account for ethnic differences is mapping by admixture linkage disequilibrium (MALD). MALD uses markers that differ markedly in allele frequency between ancestral populations, estimates the global ancestry for each individual, and compares local ancestry between subjects with different trait values to global estimates to identify regions of the genome that account for the ethnic differences of a trait. Hypothesis: Loci that are associated with VWF:Ag levels in AfAm can be mapped using MALD. Methods: From 188 AfAm healthy volunteers from the Zimmerman Program for the Molecular and Clinical Biology of VWD, 96 were selected to have 98≤VWF:Ag≥ 164 IU which represent the <25% and >75% of VWF:Ag distribution. They were genotyped using Illumina HumanCoreExome genome-wide SNP chip. SNPs were selected for MALD if they had allele frequency difference between ancestral population (YRI and CEU from HapMap) of >0.4. Related and non-admixed individuals were excluded. Extreme trait analysis was performed using ADMIXMAP. Results: 16 males and 68 females (mean age 41 years, SD=13) of whom 41 had with Ag≤98and 43 with Ag ≥164 IU were subjected to analysis with 2254 ancestry informative markers across the genome with a mean spacing of 1.8 cM (1.3 Mb). Estimated African ancestry was 79% (SD=13%, range 24-96%), while European ancestry was 20% (SD=12%, range 4-72%). Comparing the subjects at extremes of VWF, regions on chrs 1 (110-147 Mb) and 14 (22-40 Mb) had |Z| scores >3 (p<0.0025) which is the conventional cut-off in MALD studies. At chrs 1 and 14, greater African admixture was associated with higher VWF:Ag, consistent with the expected direction. No significant admixture signal was observed at the VWF (p=0.39) or ABO (p=0.48) loci, which may represent low power due to small sample size. Discussion: These pilot results require replication in a larger number of independent subjects, as well as fine-mapping to identify the underlying variants responsible for differences in VWF between individuals. Disclosures No relevant conflicts of interest to declare.

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Abstract P359: A Sickle Cell Variant Associates With Urine Albumin Excretion in Genome Wide Association Study of Hispanics: The HCHS/SOL Study

Circulation ◽

10.1161/circ.131.suppl_1.p359 ◽

2015 ◽

Vol 131 (suppl_1) ◽

Author(s):

Nora Franceschini ◽

Adrienne Stilp ◽

Christina L Wassel ◽

Holly J Mattix-Kramer ◽

Michael F Flessner ◽

...

Keyword(s):

Allele Frequency ◽

Sickle Cell ◽

Missense Variant ◽

Genome Wide Association ◽

European Ancestry ◽

Minority Population ◽

Genome Wide Association Studies ◽

Urine Albumin ◽

Genome Wide ◽

A Genome

Introduction: Genome wide association studies have identified genetic variants in the Cubillin gene ( CUBN ) that explain inter-individual variation in urine albumin-to-creatinine excretion (UACR) in populations. These studies have not included Hispanics/Latinos, the fast growing minority population in the U.S., who has also high prevalence of chronic kidney disease and its risk factors. Hypothesis: By leveraging on population admixture of Hispanics and using a genome wide association approach, we hypothesized that novel loci associated with UACR would be identified. Methods: We used data from 12,212 self-identified Hispanic individuals recruited in a community-based study, aged 18-74 years at screening (2008-2011), and randomly selected from households in four U.S. field centers (Chicago, IL; Miami, FL; Bronx, NY; San Diego, CA). Urine albumin (mg/dl) and creatinine (g/dl) were measured at the baseline exam. UACR was log-transformed for analysis. Individuals were excluded if reporting to have end-stage renal disease. Genotyping was performed using a custom Illumina Omni2.5M array. Imputation of variants was performed using 1000 Genome Project data from cosmopolitan HapMap samples. After quality control of imputed data, we performed mixed linear regression analyses that accounted for the sampling strategy and family relatedness, for variants with minor allele frequency (MAF) > 0.01 and imputation quality > 0.3. We used additive genetic models and adjusted for age, sex, and principal components which were estimated from the data. In a secondary analysis, we also examine the association of significant variants with kidney function using estimated glomerular filtration rate (eGFR) equations. Results: Among 12,212 participants, 41% were men, and mean age was 46 (SD =13). There was little evidence for genome wide inflation (lambda =1.024). We identified significant associations of single nucleotide polymorphisms (SNPs) with UACR at two loci: CUBN and HBB . The CUBN SNP (chr10:16966414, p=2.1x10-8) is an indel variant with MAF of 0.14, which was not in linkage disequilibrium with previously reported SNP rs1801239 (rsq=0.38, p=1.3x10-4) identified in individuals of European ancestry. The HBB SNP is a missense variant which results in an E [Glu] ⇒ A [Ala] substitution in the beta-globin chain of hemoglobin and a cause of the Mendelian disorder sickle cell anemia (rs334, T allele frequency =0.01, beta=0.44, SE=0.06, p=7.6x10-12). rs344 was not associated with eGFR in our data (p>0.05). Conclusion: This study identified a novel association of a sickle cell missense variant with UACR in Hispanics, and provided evidence for allelic heterogeneity at the CUBN locus. Our findings suggest a role for Mendelian gene variants in increased albuminuria in Hispanic populations with admixture.

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Abstract P260: Large-scale Meta-analysis of Diverse Ancestry Genome-wide Association Studies to Identify Pharmacogenomic Interactions of Sulfonylureas and ECG Phenotypes

Circulation ◽

10.1161/circ.133.suppl_1.p260 ◽

2016 ◽

Vol 133 (suppl_1) ◽

Author(s):

James S Floyd ◽

Colleen Sitlani ◽

Christy L Avery ◽

Eric A Whitsel ◽

Leslie Lange ◽

...

Keyword(s):

Repeated Measures ◽

Qt Interval ◽

Association Studies ◽

Meta Analysis ◽

Small Sample ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Meta Analyses

Introduction: Sulfonylureas are a commonly-used class of diabetes medication that can prolong the QT-interval, which is a leading cause of drug withdrawals from the market given the possible risk of life-threatening arrhythmias. Previously, we conducted a meta-analysis of genome-wide association studies of sulfonylurea-genetic interactions on QT interval among 9 European-ancestry (EA) cohorts using cross-sectional data, with null results. To improve our power to identify novel drug-gene interactions, we have included repeated measures of medication use and QT interval and expanded our study to include several additional cohorts, including African-American (AA) and Hispanic-ancestry (HA) cohorts with a high prevalence of sulfonylurea use. To identify potentially differential effects on cardiac depolarization and repolarization, we have also added two phenotypes - the JT and QRS intervals, which together comprise the QT interval. Hypothesis: The use of repeated measures and expansion of our meta-analysis to include diverse ancestry populations will allow us to identify novel pharmacogenomic interactions for sulfonylureas on the ECG phenotypes QT, JT, and QRS. Methods: Cohorts with unrelated individuals used generalized estimating equations to estimate interactions; cohorts with related individuals used mixed effect models clustered on family. For each ECG phenotype (QT, JT, QRS), we conducted ancestry-specific (EA, AA, HA) inverse variance weighted meta-analyses using standard errors based on the t-distribution to correct for small sample inflation in the test statistic. Ancestry-specific summary estimates were combined using MANTRA, an analytic method that accounts for differences in local linkage disequilibrium between ethnic groups. Results: Our study included 65,997 participants from 21 cohorts, including 4,020 (6%) sulfonylurea users, a substantial increase from the 26,986 participants and 846 sulfonylureas users in the previous meta-analysis. Preliminary ancestry-specific meta-analyses have identified genome-wide significant associations (P < 5х10–8) for each ECG phenotype, and analyses with MANTRA are in progress. Conclusions: In the setting of the largest collection of pharmacogenomic studies to date, we used repeated measurements and leveraged diverse ancestry populations to identify new pharmacogenomic loci for ECG traits associated with cardiovascular risk.

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Polymorphisms Associated with the Arab-Indian Haplotype of Sickle Cell Anemia Are Candidate Fetal Hemoglobin Gene Modulators

Blood ◽

10.1182/blood.v126.23.3388.3388 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3388-3388

Author(s):

Vinod Vathipadiekal ◽

Abdulrahman Alsultan ◽

John Farrell ◽

A.M Al-Rubaish ◽

Fahad Al-Muhanna ◽

...

Keyword(s):

African Americans ◽

Gene Cluster ◽

Allele Frequency ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Olfactory Receptor ◽

Receptor Gene ◽

Fetal Hemoglobin ◽

Olfactory Receptor Gene ◽

Genome Wide

Abstract Fetal hemoglobin (HbF) inhibits HbS polymerization. Because of this, sufficient HbF in most sickle erythrocytes can lead to a milder disease phenotype. HbF levels differ amongst the β-globin gene (HBB) cluster haplotypes of sickle cell anemia. In the Arab-Indian (AI) haplotype, HbF was about 20% compared with 5-10% in the Bantu, Benin, and Senegal haplotypes. Functional elements linked to the HBB haplotype are likely to regulate the expression of HbF in addition to the effects of trans-acting modulators. To identify cis-acting SNPs in the HBB gene cluster that differentiate the AI haplotype from all others, including the Senegal haplotype-the Senegal haplotype shares some SNPs with the AI haplotype but its carriers have lower HbF-we studied patients with sickle cell anemia who were homozygous for HBB haplotypes by genome-wide SNP association analysis (GWAS; Table). First, we compared the results of GWAS of 42 Saudi AI haplotype homozygotes with GWAS in 71 Saudi Benin haplotype homozygotes. The only variants distinguishing these 2 populations with genome-wide significance (p-values between 9.6E-07 and 2.7E-45) were 223 SNPs in chromosome 11p15 from positions 3.5 to 6.5 mb. This region included the HBB gene cluster, its locus control region (LCR) and the upstream and downstream olfactory receptor gene clusters. The minor allele frequency of SNPs in MYB (chr 6q23), BCL11A (chr 2p16) and KLF1 (chr 19), trans-acting loci that affect expression of the HbF genes, were similar in these 2 cohorts. A novel candidate trans-acting locus was not found, however our power to detect such an association was low. We followed-up these observations by comparing allele frequencies in 303 African American cases homozygous for the haplotypes shown in the Table. Thirteen GWAS-significant SNPs, in addition to rs7482144 and rs10128556, were present in all AI haplotype cases but not in 83 Senegal haplotype chromosomes. The allele frequency of these SNPs was replicated in 62 independent AI haplotype cases. Rs2472530 is in the coding region of OR52A5; rs16912979, rs4910743 and rs4601817 are in the HBB gene cluster LCR; rs16912979 in DNase I hypersensitive site-4 altered motifs for POLR2A, GATA1, and GATA2 binding.The minor allele of rs10837771 causes a missense mutation in OR51B4 an upstream olfactory receptor gene. To see if any of these or other alleles might sometimes be associated with HbF in the Bantu and Benin haplotyes, we selected homozygotes and compound heterozygous for these haplotypes who had unexplained and uncharacteristically high HbF. Thirty-one African Americans, aged ≥5 yrs. who had a HbF of 21% were compared with 350 similar cases who had a mean HbF of 3%. Four additional SNPs on chromosome 11, from positions ranging from 5536415 to 5543705 in the UBQLNL/HBG2, region and present in 45-48% of AI haplotype and 3-13% of other haplotypes, were found at higher frequencies in the high HbF group compared with the low HbF group. These SNPs also altered transcription factor binding motifs. Loci marked by SNPs that distinguish the AI from the Senegal and other HBB haplotypes might contain functionally important polymorphisms and account in part for high HbF in AI haplotype sickle cell anemia, independent of, or in addition to, the effects associated with rs7482144 or rs10128556. They might also be rarely associated with high HbF found in other haplotypes. These observations provide a foundation for mechanistic studies focused on the role of these variants in the expression of their linked HbF genes.Table 1.non-codedallelegenomic locationSaudi AI(n=42)Saudi ben.ben(n=71)AA ben.ben(n=264)AA ban.ban(n=31)AA sen.sen(n=8)HbF (%)1711669rs10837771Gexon OR51B410.020.0200rs4601817GLCR10.020.0400rs4910743CLCR10.010.0100rs16912979CLCR00.960.920.111rs10488675Gintron HBE110.01000rs7482144*AHBG210001rs10128556#TIntron HBBP110001rs7935470COR51V110.020.0300rs10837582GOR51V1100.0200rs11036227TOR51V110000rs10734485COR51A1P00.990.9711rs10837461AOR52A110.01000rs2472522GOR52A110.01000rs2472530Gexon OR52A510.01000rs2499948TOR52A510.020.010.020Allele frequencies in haplotypes of sickle cell anemia. * Xmn1 5' HBG 2 restriction site. This SNP, not present on the SNP microarray, was genotyped independently; # LD with rs7482144; AA designates African Americans; ben-Benin; ban-Bantu; sen-Senegal. Disclosures No relevant conflicts of interest to declare.

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Linkage disequilibrium maps for European and African populations constructed from whole genome sequence data

Scientific Data ◽

10.1038/s41597-019-0227-y ◽

2019 ◽

Vol 6 (1) ◽

Cited By ~ 1

Author(s):

Alejandra Vergara-Lope ◽

M. Reza Jabalameli ◽

Clare Horscroft ◽

Sarah Ennis ◽

Andrew Collins ◽

...

Keyword(s):

Linkage Disequilibrium ◽

Genome Sequence ◽

Sequence Data ◽

Association Studies ◽

Large Population ◽

Whole Genome Sequence ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Whole Genome ◽

Genome Wide

Abstract Quantification of linkage disequilibrium (LD) patterns in the human genome is essential for genome-wide association studies, selection signature mapping and studies of recombination. Whole genome sequence (WGS) data provides optimal source data for this quantification as it is free from biases introduced by the design of array genotyping platforms. The Malécot-Morton model of LD allows the creation of a cumulative map for each choromosome, analogous to an LD form of a linkage map. Here we report LD maps generated from WGS data for a large population of European ancestry, as well as populations of Baganda, Ethiopian and Zulu ancestry. We achieve high average genetic marker densities of 2.3–4.6/kb. These maps show good agreement with prior, low resolution maps and are consistent between populations. Files are provided in BED format to allow researchers to readily utilise this resource.

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Abstract P225: African American LDL-C GWAS Reveals a Strong Protective SNP Association in APOE; The eMERGE Study

Circulation ◽

10.1161/circ.125.suppl_10.ap225 ◽

2012 ◽

Vol 125 (suppl_10) ◽

Author(s):

Laura J Rasmussen-Torvik ◽

Jennifer A Pacheco ◽

M G Hayes ◽

Abel N Kho ◽

Arun Muthalagu ◽

...

Keyword(s):

African American ◽

African Americans ◽

Electronic Medical Records ◽

Effect Size ◽

Medical Records ◽

Association Studies ◽

Genetic Research ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide

Several Genome-Wide Association Studies (GWAS) of LDL-C have been published in populations of European-Ancestry but only one previous GWAS of LDL-C has been published in African Americans. Using phenotype data extracted from repeated lab measurements of LDL-C in electronic medical records (EMR) and the Illumina 1M Duo array we performed a LDL-C GWAS in African Americans in the eMERGE study. Methods: African Americans from eMERGE sites Northwestern University and Vanderbilt University were included in the analysis. All available LDL-C measurements as well as information about statin and hormone prescriptions, cancer, diabetes, and hypo/hyperthyroidism were abstracted from electronic medical records. Two separate samples were created; a sample incorporating exclusions due to medication use and disease diagnoses (n = 618) and a sample without exclusions (n = 1249). After data extraction and cleaning, median LDL-C for each individual was used for both analyses. GWAS analysis of median LDL-C was conducted using PLINK, controlling for age, age2, sex, recruitment site, genotyping batch, and the first three principal components of ancestry. Results: One SNP was significantly (p < 5 X 10-8) associated with LDL-C in both samples; rs7412 in the APOE gene. In the sample excluding measurements taken from those on medication or with prevalent disease, the effect size of this association was large compared to SNPs identified in previous GWAS results for LDL-C (a decrease of 19.9 mg/dl per one additional copy of the minor allele, p = 8.7 x 10 -11). The percent of LDL-C variance accounted for by rs7412 in this sample was 6.7%. The effect size of the rs7412 association was smaller in the sample without exclusions (a decrease of 12.3 mg/dl in LDL-C per allele, p = 1.6 x 10 -9) but still large compared to other LDL-C GWAS findings. Effect sizes for SNPs previously identified in the other African American GWAS of LDL-C were consistent with the earlier report, although there was not sufficient power for these associations to achieve genome-wide significance in this population. Discussion: SNP rs7412 appears to be an important common genetic variant influencing LDL-C levels. Although other signals in APOE have been detected in previous GWAS of European-Ancestry populations and African Americans and this specific SNP has been reported in several previous candidate gene studies, this association has not been identified previously in GWAS likely because rs7412 (or a good proxy) was not included on the genotyping arrays used in these studies. Our results (a) indicate that the association of rs7412 and LDL-C should be examined in other larger African American study populations, (b) further validate the use if EMR-derived traits in genetic research and (c) suggest one should be cautious in concluding that currently published GWAS have discovered all important common genetic variation contributing to certain disease traits.

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On the Distribution of Tract Lengths During Adaptive Introgression

G3 Genes|Genome|Genetics ◽

10.1534/g3.120.401616 ◽

2020 ◽

Vol 10 (10) ◽

pp. 3663-3673 ◽

Cited By ~ 1

Author(s):

Vladimir Shchur ◽

Jesper Svedberg ◽

Paloma Medina ◽

Russell Corbett-Detig ◽

Rasmus Nielsen

Keyword(s):

Linkage Disequilibrium ◽

Natural Selection ◽

Positive Selection ◽

Allele Frequency ◽

Genetic Drift ◽

Evolutionary Genetics ◽

Logistic Function ◽

Adaptive Introgression ◽

Selective Neutrality ◽

Admixture Linkage Disequilibrium

Admixture is increasingly being recognized as an important factor in evolutionary genetics. The distribution of genomic admixture tracts, and the resulting effects on admixture linkage disequilibrium, can be used to date the timing of admixture between species or populations. However, the theory used for such prediction assumes selective neutrality despite the fact that many famous examples of admixture involve natural selection acting for or against admixture. In this paper, we investigate the effects of positive selection on the distribution of tract lengths. We develop a theoretical framework that relies on approximating the trajectory of the selected allele using a logistic function. By numerically calculating the expected allele trajectory, we also show that the approach can be extended to cases where the logistic approximation is poor due to the effects of genetic drift. Using simulations, we show that the model is highly accurate under most scenarios. We use the model to show that positive selection on average will tend to increase the admixture tract length. However, perhaps counter-intuitively, conditional on the allele frequency at the time of sampling, positive selection will actually produce shorter expected tract lengths. We discuss the consequences of our results in interpreting the timing of the introgression of EPAS1 from Denisovans into the ancestors of Tibetans.

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On the distribution of tract lengths during adaptive introgression

10.1101/724815 ◽

2019 ◽

Cited By ~ 4

Author(s):

Vladimir Shchur ◽

Jesper Svedberg ◽

Paloma Medina ◽

Russ Corbett-Detig ◽

RASMUS Nielsen

Keyword(s):

Linkage Disequilibrium ◽

Natural Selection ◽

Positive Selection ◽

Allele Frequency ◽

Genetic Drift ◽

Evolutionary Genetics ◽

Logistic Function ◽

Adaptive Introgression ◽

Selective Neutrality ◽

Admixture Linkage Disequilibrium

ABSTRACTAdmixture is increasingly being recognized as an important factor in evolutionary genetics. The distribution of genomic admixture tracts, and the resulting effects on admixture linkage disequilibrium, can be used to date the timing of admixture between species or populations. However, the theory used for such prediction assumes selective neutrality despite the fact that many famous examples of admixture involve natural selection acting for or against admixture. In this paper, we investigate the effects of positive selection on the distribution of tract lengths. We develop a theoretical framework that relies on approximating the trajectory of the selected allele using a logistic function. By numerically calculating the expected allele trajectory, we also show that the approach can be extended to cases where the logistic approximation is poor due to the effects of genetic drift. Using simulations, we show that the model is highly accurate under most scenarios. We use the model to show that positive selection on average will tend to increase the admixture tract length. However, perhaps counter-intuitively, conditional on the allele frequency at the time of sampling, positive selection will actually produce shorter expected tract lengths. We discuss the consequences of our results in interpreting the timing of the introgression of EPAS1 from Denisovans into the ancestors of Tibetans.

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Significant Admixture Linkage Disequilibrium across 30 cM around the FY Locus in African Americans

The American Journal of Human Genetics ◽

10.1086/302820 ◽

2000 ◽

Vol 66 (3) ◽

pp. 969-978 ◽

Cited By ~ 64

Author(s):

James A. Lautenberger ◽

J. Claiborne Stephens ◽

Stephen J. O'Brien ◽

Michael W. Smith

Keyword(s):

Linkage Disequilibrium ◽

African Americans ◽

Admixture Linkage Disequilibrium

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Genetic Determinants of Radiographic Knee Osteoarthritis in African Americans

The Journal of Rheumatology ◽

10.3899/jrheum.161488 ◽

2017 ◽

Vol 44 (11) ◽

pp. 1652-1658 ◽

Cited By ~ 6

Author(s):

Youfang Liu ◽

Michelle S. Yau ◽

Laura M. Yerges-Armstrong ◽

David J. Duggan ◽

Jordan B. Renner ◽

...

Keyword(s):

African Americans ◽

Knee Osteoarthritis ◽

Allele Frequency ◽

Minor Allele Frequency ◽

Fixed Effects ◽

Minor Allele ◽

Knee Oa ◽

Genome Wide ◽

A Genome ◽

Pathway Analyses

Objective.The etiology of knee osteoarthritis (OA), the most common form of arthritis, is complex and may differ by race or ethnicity. In recent years, genetic studies have identified many genetic variants associated with OA, but nearly all the studies were conducted in European whites and Asian Americans. Few studies have focused on the genetics of knee OA in African Americans.Methods.We performed a genome-wide association study of radiographic knee OA in 1217 African Americans from 2 North American cohort studies: 590 subjects from the Johnston County Osteoarthritis Project and 627 subjects from the Osteoarthritis Initiative. Analyses were conducted in each cohort separately and combined in an inverse variance fixed effects metaanalysis, which were then included in pathway analyses. We additionally tested 12 single-nucleotide polymorphisms robustly associated with OA in European white populations for association in African Americans.Results.We identified a genome-wide significant variant in LINC01006 (minor allele frequency 12%; p = 4.11 × 10−9) that is less common in European white populations (minor allele frequency < 3%). Five other independent loci reached suggestive significance (p < 1 × 10−6). In pathway analyses, dorsal/ventral neural tube patterning and iron ion transport pathways were significantly associated with knee OA in African Americans (false discovery rate < 0.05). We found no evidence that previously reported OA susceptibility variants in European whites were associated with knee OA in African Americans.Conclusion.These results highlight differences in the genetic architecture of knee OA between African American and European whites. This finding underscores the need to include more diverse populations in OA genetics studies.

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Genetic Susceptibility Markers of Multiple Myeloma in African-Americans

Blood ◽

10.1182/blood.v124.21.2030.2030 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2030-2030

Author(s):

Kristin A Rand ◽

Chi Song ◽

Amie E. Hwang ◽

Carol A. Huff ◽

Leon Bernal-Mizrachi ◽

...

Keyword(s):

Prostate Cancer ◽

Multiple Myeloma ◽

African Americans ◽

Fine Mapping ◽

Research Funding ◽

African Ancestry ◽

Case Control ◽

European Ancestry ◽

Risk Variants ◽

Genome Wide

Abstract Multiple myeloma (MM) is 2-3 times more common among African-Americans compared to non-Hispanic whites. The 2-3-fold increased risk among family members of cases suggests a genetic contribution to risk. Genome-wide association studies (GWAS) in populations of European ancestry have identified seven novel risk loci at 2p23.3 (rs6746082), 3q26.2 (rs10936599), 3p22.1 (rs1052501), 6p21.32 (rs2285803), 7p15.3 (rs4487645), 17p11.2 (rs4273077) and 22q13.1 (rs877529) (Broderick, et al. Nat Genet, 2011, Chubb, et al. Nat Genet, 2013), three of which were replicated in another European series (Martino et al., Br J Haematol, 2012). Here we examined the index signals and conducted fine-mapping for each locus in a case-control study of 1,049 multiple myeloma cases and 7,084 controls of African ancestry to identify better markers of risk and novel independent loci in seven previously reported regions in this high risk population. Incident cases were recruited from 10 clinical centers and SEER cancer registries from 2011 to 2013 and genotyped using the Illumina HumanCore GWAS array. Control data were obtained from previous genome-wide studies of breast and prostate cancer, genotyped using the Illumina 1M-Duo in 4425 male controls from the African Ancestry Prostate Cancer Consortium (consisting of 14 independent studies) and 2632 female controls from a breast cancer GWAS of African-American women (consisting of 9 independent studies). Imputation to 1000 Genomes (March 2012 release) was conducted for regions around six of the previously identified single nucleotide polymorphisms [SNPs] (the HLA region harboring rs2285803 is still being imputed, results will be presented). A case-control analysis of SNPs/indels >1% frequency within 250 kb of each index variant was conducted using unconditional multivariable logistic regression adjusting for age, sex and five leading principal components. Region-specific alpha levels were determined through permutation tests. The minimum alpha level across the six regions was α=0.002. All previously reported risk variants were common in African-Americans (minor allele frequency [MAF] >0.05). For five of the six SNPs, we had ≥94% power to detect the same effect observed in non-Hispanic whites, and 64% power for the less common variant rs10936599 (MAF=0.07). We observed directionally consistent effects (odds ratio [OR]>1) for the six risk variants tested, with three replicating at p≤0.05 (7p15.3, p=1.4x10-7; 17p11.2, p=0.05; 22q13.1, p=0.02). For three of the six regions, we observed better markers of risk in African-Americans that were correlated with the index SNP in Europeans (7p15.3, rs56333627, p=1.5x10-5, r2=0.89; 17p11.2, rs34562254, p=2.9x10-3, r2=0.90; 22q13.1, rs2092410, p=1.1x10-4 r2=.71). The missense variant identified in the 17p11.2 region (rs34562254, Pro251Leu) is located in TNFRSF13B, which encodes the protein TACI, a B cell surface receptor which plays a role in B cell maturation, apoptosis and antibody production by inducing activation of transcription factors including NFAT and NFκβ. In addition, there is evidence suggesting that TACI is involved in MM pathogenesis. Our results demonstrate that many of the risk loci for MM found in European ancestry populations are also risk loci in men and women of African ancestry and that by fine-mapping, we are able to identify variants that better capture risk in populations of African ancestry. Disclosures Terebelo: Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

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