Deep targeted sequencing of 12 breast cancer susceptibility regions in 4611 women across four different ethnicities
View/ Open
Author
Lindström, Sara
Chen, Gary
Henderson, Brian E.
Le Marchand, Loic
Hofmann, Oliver
Haiman, Christopher A.
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.1186/s13058-016-0772-7Metadata
Show full item recordCitation
Lindström, S., A. Ablorh, B. Chapman, A. Gusev, G. Chen, C. Turman, A. H. Eliassen, et al. 2016. “Deep targeted sequencing of 12 breast cancer susceptibility regions in 4611 women across four different ethnicities.” Breast Cancer Research : BCR 18 (1): 109. doi:10.1186/s13058-016-0772-7. http://dx.doi.org/10.1186/s13058-016-0772-7.Abstract
Background: 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. Methods: 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. Results: 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. Conclusions: 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. Electronic supplementary material The online version of this article (doi:10.1186/s13058-016-0772-7) contains supplementary material, which is available to authorized users.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097387/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:29626222
Collections
- HMS Scholarly Articles [17917]
- SPH Scholarly Articles [6362]
Contact administrator regarding this item (to report mistakes or request changes)