Abstract
Recent genetic admixture coupled with striking differences in incidence of estrogen receptor (ER) breast cancer subtypes, as well as severity, between women of African and European ancestry, provides an excellent rationale for performing admixture mapping in African American women with breast cancer risk. We performed the largest breast cancer admixture mapping study with in African American women to identify novel genomic regions associated with the disease. We conducted a genome-wide admixture scan using 2,624 autosomal ancestry informative markers (AIMs) in 3,629 breast cancer cases (including 1,968 ER-positive, 1093 ER-negative, and 601 triple-negative) and 4,658 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, a collaborative study of four large geographically different epidemiological studies of breast cancer in African American women. We used an independent case-control study to test for SNP association in regions with genome-wide significant admixture signals. We found two novel genome-wide significant regions of excess African ancestry, 4p16.1 and 17q25.1, associated with ER-positive breast cancer. Two regions known to harbor breast cancer variants, 10q26 and 11q13, were also identified with excess of African ancestry. Fine-mapping of the identified genome-wide significant regions suggests the presence of significant genetic associations with ER-positive breast cancer in 4p16.1 and 11q13. In summary, we identified three novel genomic regions associated with breast cancer risk by ER status, suggesting that additional previously unidentified variants may contribute to the racial differences in breast cancer risk in the African American population.
Highlights
A majority of the close to 100 breast cancer risk loci that have been identified to date were found using genomewide approaches in populations of European ancestry women (Maxwell and Nathanson, 2013; Michailidou et al, 2015; Couch et al, 2016)
The 10q26 and 11q13.2 regions both contain SNPs previously identified in published genome-wide association studies (GWAS) of breast cancer in European ancestry women (Hunter et al, 2007; Turnbull et al, 2010), and fine-mapping efforts have identified independent signals in African American women (Chen et al, 2011)
There are no reports of variants at 2q37.1 or 18p11 associated with breast cancer or breast cancer subtypes. Given these regions of excess African ancestry are associated with disease; it may be possible that these locations harbor breast cancer susceptibility alleles only present in African ancestry populations. In this large genome-wide admixture scan in African American women, we found evidence of associations of local African ancestry with breast cancer in several genomic regions
Summary
A majority of the close to 100 breast cancer risk loci that have been identified to date were found using genomewide approaches in populations of European ancestry women (Maxwell and Nathanson, 2013; Michailidou et al, 2015; Couch et al, 2016). Admixture mapping efforts in African American women with breast cancer were likely under-powered, in particular to detect loci associated with breast cancer subtypes (Fejerman et al, 2009). This approach, in conjunction with fine mapping, has been successful at identifying genetic associations with other complex traits in recently admixed populations (Zhu et al, 2005; Freedman et al, 2006; Nalls et al, 2008; Manuck et al, 2011; Bensen et al, 2014; Jeff et al, 2014; Parker et al, 2014)
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