Targeted resequencing of the coding sequence of 38 genes near breast cancer GWAS loci in a large case–control study

Abstract

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