Deep targeted sequencing of 12 breast cancer susceptibility regions in 4611 women across four different ethnicities.
Although genome-wide association studies (GWASs) have identified thousands of disease susceptibility regions, the underlying causal mechanism in these regions is not fully known. It is likely that the GWAS signal originates from one or many as yet unidentified causal variants.



Using next-generation sequencing, we characterized 12 breast cancer susceptibility regions identified by GWASs in 2288 breast cancer cases and 2323 controls across four populations of African American, European, Japanese, and Hispanic ancestry.



After genotype calling and quality control, we identified 137,530 single-nucleotide variants (SNVs); of those, 87.2 % had a minor allele frequency (MAF) <0.005. For SNVs with MAF >0.005, we calculated the smallest number of SNVs needed to obtain a posterior probability set (PPS) such that there is 90 % probability that the causal SNV is included. We found that the PPS for two regions, 2q35 and 11q13, contained less than 5 % of the original SNVs, dramatically decreasing the number of potentially causal SNVs. However, we did not find strong evidence supporting a causal role for any individual SNV. In addition, there were no significant gene-based rare SNV associations after correcting for multiple testing.



This study illustrates some of the challenges faced in fine-mapping studies in the post-GWAS era, most importantly the large sample sizes needed to identify rare-variant associations or to distinguish the effects of strongly correlated common SNVs.
Department of Epidemiology, University of Washington, 1959 N.E. Pacific Street, Health Sciences Building, Room F247B, Seattle, WA, 98195, USA. saralind@uw.edu.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. saralind@uw.edu.
Sara
S
Lindström
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
Akweley
A
Ablorh
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.|HSPH Bioinformatics Core, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
Brad
B
Chapman
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
Alexander
A
Gusev
Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
Gary
G
Chen
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
Constance
C
Turman
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
A Heather
AH
Eliassen
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
Alkes L
AL
Price
Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
Brian E
BE
Henderson
Cancer Research Center of Hawai'i, University of Hawai'i, Honolulu, HI, 96813, USA.
Loic
L
Le Marchand
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.|HSPH Bioinformatics Core, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
Oliver
O
Hofmann
Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
Christopher A
CA
Haiman
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
Peter
P
Kraft
D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D009726:Nurses; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide
Breast cancer; Fine-mapping; GWAS; Multiethnic analysis; Next-generation sequencing