title: Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies novel susceptibility markers.
abstract: Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified in regions including 5p12 (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.11-1.76; P = 0.004), 5q11.2 (OR = 1.22, 95% CI = 1.09-1.36; P = 0.00053) and 10p15.1 (OR = 1.22, 95% CI = 1.08-1.38; P = 0.0015). We also found positive association signals in three regions (6q25.1, 10q26.13 and 16q12.1-q12.2) previously confirmed by fine mapping in women of African ancestry. In addition, polygenic model indicated that eight best markers in this study, compared with 22 GWAS-identified SNPs, could better predict breast cancer risk in women of African ancestry (per-allele OR = 1.21, 95% CI = 1.16-1.27; P = 9.7 × 10(-16)). Our results demonstrate that fine mapping is a powerful approach to better characterize the breast cancer risk alleles in diverse populations. Future studies and new GWAS in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African diaspora.
authors.affiliation: Department of Medicine, Center for Clinical Cancer Genetics and Global Health, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yonglan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Temidayo O
authors.initials: TO
authors.lastname: Ogundiran
authors.forename: Adeyinka G
authors.initials: AG
authors.lastname: Falusi
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Esther M
authors.initials: EM
authors.lastname: John
authors.forename: Anselm J M
authors.initials: AJ
authors.lastname: Hennis
authors.forename: Stefan
authors.initials: S
authors.lastname: Ambs
authors.forename: Susan M
authors.initials: SM
authors.lastname: Domchek
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rebbeck
authors.forename: Michael S
authors.initials: MS
authors.lastname: Simon
authors.forename: Barbara
authors.initials: B
authors.lastname: Nemesure
authors.forename: Suh-Yuh
authors.initials: SY
authors.lastname: Wu
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Leske
authors.forename: Abayomi
authors.initials: A
authors.lastname: Odetunde
authors.forename: Qun
authors.initials: Q
authors.lastname: Niu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Chibuzor
authors.initials: C
authors.lastname: Afolabi
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: Christopher O
authors.initials: CO
authors.lastname: Olopade
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
authors.forename: Dezheng
authors.initials: D
authors.lastname: Huo
mesh_terms: D000328:Adult; D000483:Alleles; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D044383:Black People / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping / Q000379:methods; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics / Q000378:metabolism; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics / Q000378:metabolism; D016001:Confidence Intervals; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide
chemical_list: D014408:Biomarkers, Tumor