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Targeted Resequencing of the Coding Sequence of 38 Genes Near Breast Cancer GWAS Loci in a Large Case-Control Study.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Luccarini, Craig 
Pooley, Karen A 
Shah, Mitul 

Abstract

BACKGROUND: Genes regulated by breast cancer risk alleles identified through genome-wide association studies (GWAS) may harbor rare coding risk alleles. METHODS: We sequenced the coding regions for 38 genes within 500 kb of 38 lead GWAS SNPs in 13,538 breast cancer cases and 5,518 controls. RESULTS: Truncating variants in these genes were rare, and were not associated with breast cancer risk. Burden testing of rare missense variants highlighted 5 genes with some suggestion of an association with breast cancer, although none met the multiple testing thresholds: MKL1, FTO, NEK10, MDM4, and COX11. Six common alleles in COX11, MAP3K1 (two), and NEK10 (three) were associated at the P < 0.0001 significance level, but these likely reflect linkage disequilibrium with causal regulatory variants. CONCLUSIONS: There was no evidence that rare coding variants in these genes confer substantial breast cancer risks. However, more modest effect sizes could not be ruled out. IMPACT: We tested the hypothesis that rare variants in 38 genes near breast cancer GWAS loci may mediate risk. These variants do not appear to play a major role in breast cancer heritability.

Description

Keywords

Breast Neoplasms, Case-Control Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans

Journal Title

Cancer Epidemiol Biomarkers Prev

Conference Name

Journal ISSN

1055-9965
1538-7755

Volume Title

28

Publisher

American Association for Cancer Research (AACR)
Sponsorship
Cancer Research Uk (None)
Cancer Research UK (A16563)