Re-evaluating genetic variants identified in candidate gene studies of breast cancer risk using data from nearly 280,000 women of Asian and European ancestryResearch in context

Background: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genom...

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Published in:EBioMedicine 2019-10, Vol.48, p.203-211
Main Authors: Yaohua Yang, Xiang Shu, Xiao-ou Shu, Manjeet K. Bolla, Sun-Seog Kweon, Qiuyin Cai, Kyriaki Michailidou, Qin Wang, Joe Dennis, Boyoung Park, Keitaro Matsuo, Ava Kwong, Sue Kyung Park, Anna H. Wu, Soo Hwang Teo, Motoki Iwasaki, Ji-Yeob Choi, Jingmei Li, Mikael Hartman, Chen-Yang Shen, Kenneth Muir, Artitaya Lophatananon, Bingshan Li, Wanqing Wen, Yu-Tang Gao, Yong-Bing Xiang, Kristan J. Aronson, John J. Spinell, Manuela Gago-Dominguez, Esther M. John, Allison W. Kurian, Jenny Chang-Claude, Shou-Tung Chen, Thilo Dörk, D. Gareth R. Evans, Marjanka K. Schmidt, Min-Ho Shin, Graham G. Giles, Roger L. Milne, Jacques Simard, Michiaki Kubo, Peter Kraft, Daehee Kang, Douglas F. Easton, Wei Zheng, Jirong Long
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container_title EBioMedicine
container_volume 48
creator Yaohua Yang
Xiang Shu
Xiao-ou Shu
Manjeet K. Bolla
Sun-Seog Kweon
Qiuyin Cai
Kyriaki Michailidou
Qin Wang
Joe Dennis
Boyoung Park
Keitaro Matsuo
Ava Kwong
Sue Kyung Park
Anna H. Wu
Soo Hwang Teo
Motoki Iwasaki
Ji-Yeob Choi
Jingmei Li
Mikael Hartman
Chen-Yang Shen
Kenneth Muir
Artitaya Lophatananon
Bingshan Li
Wanqing Wen
Yu-Tang Gao
Yong-Bing Xiang
Kristan J. Aronson
John J. Spinell
Manuela Gago-Dominguez
Esther M. John
Allison W. Kurian
Jenny Chang-Claude
Shou-Tung Chen
Thilo Dörk
D. Gareth R. Evans
Marjanka K. Schmidt
Min-Ho Shin
Graham G. Giles
Roger L. Milne
Jacques Simard
Michiaki Kubo
Peter Kraft
Daehee Kang
Douglas F. Easton
Wei Zheng
Jirong Long
description Background: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets. Methods: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets. Findings: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P 
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Bolla ; Sun-Seog Kweon ; Qiuyin Cai ; Kyriaki Michailidou ; Qin Wang ; Joe Dennis ; Boyoung Park ; Keitaro Matsuo ; Ava Kwong ; Sue Kyung Park ; Anna H. Wu ; Soo Hwang Teo ; Motoki Iwasaki ; Ji-Yeob Choi ; Jingmei Li ; Mikael Hartman ; Chen-Yang Shen ; Kenneth Muir ; Artitaya Lophatananon ; Bingshan Li ; Wanqing Wen ; Yu-Tang Gao ; Yong-Bing Xiang ; Kristan J. Aronson ; John J. Spinell ; Manuela Gago-Dominguez ; Esther M. John ; Allison W. Kurian ; Jenny Chang-Claude ; Shou-Tung Chen ; Thilo Dörk ; D. Gareth R. Evans ; Marjanka K. Schmidt ; Min-Ho Shin ; Graham G. Giles ; Roger L. Milne ; Jacques Simard ; Michiaki Kubo ; Peter Kraft ; Daehee Kang ; Douglas F. Easton ; Wei Zheng ; Jirong Long</creator><creatorcontrib>Yaohua Yang ; Xiang Shu ; Xiao-ou Shu ; Manjeet K. Bolla ; Sun-Seog Kweon ; Qiuyin Cai ; Kyriaki Michailidou ; Qin Wang ; Joe Dennis ; Boyoung Park ; Keitaro Matsuo ; Ava Kwong ; Sue Kyung Park ; Anna H. Wu ; Soo Hwang Teo ; Motoki Iwasaki ; Ji-Yeob Choi ; Jingmei Li ; Mikael Hartman ; Chen-Yang Shen ; Kenneth Muir ; Artitaya Lophatananon ; Bingshan Li ; Wanqing Wen ; Yu-Tang Gao ; Yong-Bing Xiang ; Kristan J. Aronson ; John J. Spinell ; Manuela Gago-Dominguez ; Esther M. John ; Allison W. Kurian ; Jenny Chang-Claude ; Shou-Tung Chen ; Thilo Dörk ; D. Gareth R. Evans ; Marjanka K. Schmidt ; Min-Ho Shin ; Graham G. Giles ; Roger L. Milne ; Jacques Simard ; Michiaki Kubo ; Peter Kraft ; Daehee Kang ; Douglas F. Easton ; Wei Zheng ; Jirong Long</creatorcontrib><description>Background: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets. Methods: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets. Findings: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P &lt; 2·19 × 10−4. The associations for four variants reached P &lt; 5 × 10−8 and have been reported by previous GWAS, including rs6435074 and rs6723097 (CASP8), rs17879961 (CHEK2) and rs2853669 (TERT). The remaining eight variants were rs676387 (HSD17B1), rs762551 (CYP1A2), rs1045485 (CASP8), rs9340799 (ESR1), rs7931342 (CHR11), rs1050450 (GPX1), rs13010627 (CASP10) and rs9344 (CCND1). Further investigating these 10 genes identified associations for two additional variants at P &lt; 5 × 10−8, including rs4793090 (near HSD17B1), and rs9210 (near CYP1A2), which have not been identified by previous GWAS. Interpretation: Though most candidate gene variants were not associated with breast cancer risk, we found 14 variants showing an association. Our findings warrant further functional investigation of these variants. Fund: National Institutes of Health. 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Evans</creatorcontrib><creatorcontrib>Marjanka K. Schmidt</creatorcontrib><creatorcontrib>Min-Ho Shin</creatorcontrib><creatorcontrib>Graham G. Giles</creatorcontrib><creatorcontrib>Roger L. Milne</creatorcontrib><creatorcontrib>Jacques Simard</creatorcontrib><creatorcontrib>Michiaki Kubo</creatorcontrib><creatorcontrib>Peter Kraft</creatorcontrib><creatorcontrib>Daehee Kang</creatorcontrib><creatorcontrib>Douglas F. Easton</creatorcontrib><creatorcontrib>Wei Zheng</creatorcontrib><creatorcontrib>Jirong Long</creatorcontrib><title>Re-evaluating genetic variants identified in candidate gene studies of breast cancer risk using data from nearly 280,000 women of Asian and European ancestryResearch in context</title><title>EBioMedicine</title><description>Background: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets. Methods: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets. Findings: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P &lt; 2·19 × 10−4. The associations for four variants reached P &lt; 5 × 10−8 and have been reported by previous GWAS, including rs6435074 and rs6723097 (CASP8), rs17879961 (CHEK2) and rs2853669 (TERT). The remaining eight variants were rs676387 (HSD17B1), rs762551 (CYP1A2), rs1045485 (CASP8), rs9340799 (ESR1), rs7931342 (CHR11), rs1050450 (GPX1), rs13010627 (CASP10) and rs9344 (CCND1). Further investigating these 10 genes identified associations for two additional variants at P &lt; 5 × 10−8, including rs4793090 (near HSD17B1), and rs9210 (near CYP1A2), which have not been identified by previous GWAS. Interpretation: Though most candidate gene variants were not associated with breast cancer risk, we found 14 variants showing an association. Our findings warrant further functional investigation of these variants. Fund: National Institutes of Health. 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Methods: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets. Findings: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P &lt; 2·19 × 10−4. The associations for four variants reached P &lt; 5 × 10−8 and have been reported by previous GWAS, including rs6435074 and rs6723097 (CASP8), rs17879961 (CHEK2) and rs2853669 (TERT). The remaining eight variants were rs676387 (HSD17B1), rs762551 (CYP1A2), rs1045485 (CASP8), rs9340799 (ESR1), rs7931342 (CHR11), rs1050450 (GPX1), rs13010627 (CASP10) and rs9344 (CCND1). 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title Re-evaluating genetic variants identified in candidate gene studies of breast cancer risk using data from nearly 280,000 women of Asian and European ancestryResearch in context
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