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Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans.

ABSTRACT: Genome-wide association studies (GWAS) have revealed 19 common genetic variants that are associated with breast cancer risk. Testing of the index signals found through GWAS and fine-mapping of each locus in diverse populations will be necessary for characterizing the role of these risk regions in contributing to inherited susceptibility. In this large study of breast cancer in African-American women (3016 cases and 2745 controls), we tested the 19 known risk variants identified by GWAS and replicated associations (P < 0.05) with only 4 variants. Through fine-mapping, we identified markers in four regions that better capture the association with breast cancer risk in African Americans as defined by the index signal (2q35, 5q11, 10q26 and 19p13). We also identified statistically significant associations with markers in four separate regions (8q24, 10q22, 11q13 and 16q12) that are independent of the index signals and may represent putative novel risk variants. In aggregate, the more informative markers found in the study enhance the association of these risk regions with breast cancer in African Americans [per allele odds ratio (OR) = 1.18, P = 2.8 × 10(-24) versus OR = 1.04, P = 6.1 × 10(-5)]. In this detailed analysis of the known breast cancer risk loci, we have validated and improved upon markers of risk that better characterize their association with breast cancer in women of African ancestry.

SUBMITTER: Chen F

PROVIDER: S-EPMC3196889 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans.

Chen Fang F Chen Gary K GK Millikan Robert C RC John Esther M EM Ambrosone Christine B CB Bernstein Leslie L Zheng Wei W Hu Jennifer J JJ Ziegler Regina G RG Deming Sandra L SL Bandera Elisa V EV Nyante Sarah S Palmer Julie R JR Rebbeck Timothy R TR Ingles Sue A SA Press Michael F MF Rodriguez-Gil Jorge L JL Chanock Stephen J SJ Le Marchand Loïc L Kolonel Laurence N LN Henderson Brian E BE Stram Daniel O DO Haiman Christopher A CA

Human molecular genetics 20110818 22

Genome-wide association studies (GWAS) have revealed 19 common genetic variants that are associated with breast cancer risk. Testing of the index signals found through GWAS and fine-mapping of each locus in diverse populations will be necessary for characterizing the role of these risk regions in contributing to inherited susceptibility. In this large study of breast cancer in African-American women (3016 cases and 2745 controls), we tested the 19 known risk variants identified by GWAS and repli ...[more]

PMID: 21852243

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Project description:The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P?1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P?1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.

Dataset Information

Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans.

Publications

Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans.

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