Trans-ethnic follow-up of breast cancer GWAS hits using the preferential linkage disequilibrium approach - PubMed (original) (raw)

Multicenter Study

. 2016 Dec 13;7(50):83160-83176.

doi: 10.18632/oncotarget.13075.

Lori Shepherd 1, Kathryn L Lunetta 2, Song Yao 3, Qian Liu 1, Qiang Hu 1, Stephen A Haddad 4, Lara Sucheston-Campbell 3, Jeannette T Bensen 5, Elisa V Bandera 6, Lynn Rosenberg 4, Song Liu 1, Christopher A Haiman 7, Andrew F Olshan 5, Julie R Palmer 4, Christine B Ambrosone 3

Affiliations

Multicenter Study

Trans-ethnic follow-up of breast cancer GWAS hits using the preferential linkage disequilibrium approach

Qianqian Zhu et al. Oncotarget. 2016.

Abstract

Leveraging population-distinct linkage equilibrium (LD) patterns, trans-ethnic follow-up of variants discovered from genome-wide association studies (GWAS) has proved to be useful in facilitating the identification of bona fide causal variants. We previously developed the preferential LD approach, a novel method that successfully identified causal variants driving the GWAS signals within European-descent populations even when the causal variants were only weakly linked with the GWAS-discovered variants. To evaluate the performance of our approach in a trans-ethnic setting, we applied it to follow up breast cancer GWAS hits identified mostly from populations of European ancestry in African Americans (AA). We evaluated 74 breast cancer GWAS variants in 8,315 AA women from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. Only 27% of them were associated with breast cancer risk at significance level α=0.05, suggesting race-specificity of the identified breast cancer risk loci. We followed up on those replicated GWAS hits in the AMBER consortium utilizing the preferential LD approach, to search for causal variants or better breast cancer markers from the 1000 Genomes variant catalog. Our approach identified stronger breast cancer markers for 80% of the GWAS hits with at least nominal breast cancer association, and in 81% of these cases, the marker identified was among the top 10 of all 1000 Genomes variants in the corresponding locus. The results support trans-ethnic application of the preferential LD approach in search for candidate causal variants, and may have implications for future genetic research of breast cancer in AA women.

Keywords: causal variant; fine-mapping; genome-wide association studies.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

Figures

Figure 1

Figure 1. The QQ plot of overall breast cancer association p-values in AMBER consortium

The variants selected by the preferential LD approach in the 18 replicated loci are in red. The 1000 Genomes variants in the same 18 loci are in black. The blue horizontal line corresponds to the study-wide significance cutoff 2.55×10−6.

Figure 2

Figure 2. Breast cancer association of variants within 500 kb of rs10069690

A. and rs2363956 B. in the AMBER cohort. The GWAS-discovered variants were denoted by the purple circles.

Figure 3

Figure 3. Association between variants within 500 kb of rs3112572 and ER+ breast cancer

A., between variants within 500 kb of rs10069690 B. and rs2363956 C. and ER- breast cancer in the AMBER cohort. The GWAS-discovered variants were denoted by the purple circles.

Figure 4

Figure 4. Breast cancer association of variants within 500 kb of rs2981582 in the AMBER cohort

The GWAS-discovered variant rs2981582 is denoted by the purple circle. The -logP values before A. and after B. conditioning on the causal variant rs2981578 were shown.

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