Genome-Wide Association Study of Breast Cancer in the Japanese Population

Abstract

Breast cancer is the most common malignancy among women in worldwide including Japan. Several studies have identified common genetic variants to be associated with the risk of breast cancer. Due to the complex linkage disequilibrium structure and various environmental exposures in different populations, it is essential to identify variants associated with breast cancer in each population, which subsequently facilitate the better understanding of mammary carcinogenesis. In this study, we conducted a genome-wide association study (GWAS) as well as whole-genome imputation with 2,642 cases and 2,099 unaffected female controls. We further examined 13 suggestive loci (P<1.0×10−5) using an independent sample set of 2,885 cases and 3,395 controls and successfully validated two previously-reported loci, rs2981578 (combined P-value of 1.31×10−12, OR = 1.23; 95% CI = 1.16–.30) on chromosome 10q26 (FGFR2), rs3803662 (combined P-value of 2.79×10−11, OR = 1.21; 95% CI = 1.15–.28) and rs12922061 (combined P-value of 3.97×10−10, OR = 1.23; 95% CI = 1.15–.31) on chromosome 16q12 (TOX3-LOC643714). Weighted genetic risk score on the basis of three significantly associated variants and two previously reported breast cancer associated loci in East Asian population revealed that individuals who carry the most risk alleles in category 5 have 2.2 times higher risk of developing breast cancer in the Japanese population than those who carry the least risk alleles in reference category 1. Although we could not identify additional loci associated with breast cancer, our study utilized one of the largest sample sizes reported to date, and provided genetic status that represent the Japanese population. Further local and international collaborative study is essential to identify additional genetic variants that could lead to a better, accurate prediction for breast cancer.

Previous GWAS hits in relation to young-onset breast cancer

“…Our FGFR2 SNP, rs2981579, was first identified by Thomas et al [31] and independently replicated in two other GWAS [23, 32]. Other GWAS found stronger associations with other SNPs in the same gene [1, 7, 8, 10, 12, 15, 19, 22, 26]. Ahsan et al [1], for example, reported genome-wide significant p-values for 4 FGFR2 SNPs and young-onset breast cancer, with the smallest p-value seen for rs2981579.…”

“…Its link to breast cancer is unclear, though there is some evidence that it is a tumor suppressor [66, 67]. Our top hit, rs3803662, was first identified by Easton et al, [7], with several subsequent GWAS confirming the region’s importance [11, 18, 22, 23, 30–32]. Presence of this variant allele has been linked to lower TOX3 expression levels in breast tumor tissue [68].…”

“…Several previous studies have used similar approaches, but most have considered only models with multiplicative joint effects [18, 22, 60, 77, 79]. Like us, Joshi et al [80] constructed scores for both multiplicative and additive polygenic effects using externally-reported effect estimates.…”

Breast cancer risk prediction using a clinical risk model and polygenic risk score

“…For this analysis, we included SNPs reported as genome wide significant (p < 5×10 −8 ) in studies of invasive breast cancer in Caucasian, Asian or Hispanic populations [11,12,15,16,24,17,18,25,10,14,19,26] which we identified by review of the GWAS catalogue [27]. If a SNP was not on the array, we sought a proxy SNP in strong linkage disequilibrium (LD), r 2 > 0.9.…”

“…We constructed two separate PRS, one with the allele frequencies and odds ratios (ORs) from Caucasian populations used in the main analysis, and another with allele frequencies and ORs from East Asian populations ( Table S2) [15,16,18]. The Asian-specific PRS had 76 SNPs after the exclusion of SNPs that were non-polymorphic in Asian populations.…”