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Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1.

ABSTRACT: In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene; P=8.82×10(-9)), rs10474352 at 5q14.3 (near the ARRDC3 gene; P=1.67×10(-9)) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P=4.25×10(-8)). We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P=0.030, 0.004 and 0.010, respectively). Data from the ENCODE Project suggest that variants rs4951011 and rs10474352 might be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.

SUBMITTER: Cai Q

PROVIDER: S-EPMC4127632 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1.

Cai Qiuyin Q Zhang Ben B Sung Hyuna H Low Siew-Kee SK Kweon Sun-Seog SS Lu Wei W Shi Jiajun J Long Jirong J Wen Wanqing W Choi Ji-Yeob JY Noh Dong-Young DY Shen Chen-Yang CY Matsuo Keitaro K Teo Soo-Hwang SH Kim Mi Kyung MK Khoo Ui Soon US Iwasaki Motoki M Hartman Mikael M Takahashi Atsushi A Ashikawa Kyota K Matsuda Koichi K Shin Min-Ho MH Park Min Ho MH Zheng Ying Y Xiang Yong-Bing YB Ji Bu-Tian BT Park Sue K SK Wu Pei-Ei PE Hsiung Chia-Ni CN Ito Hidemi H Kasuga Yoshio Y Kang Peter P Mariapun Shivaani S Ahn Sei Hyun SH Kang Han Sung HS Chan Kelvin Y K KY Man Ellen P S EP Iwata Hiroji H Tsugane Shoichiro S Miao Hui H Liao Jiemin J Nakamura Yusuke Y Kubo Michiaki M Delahanty Ryan J RJ Zhang Yanfeng Y Li Bingshan B Li Chun C Gao Yu-Tang YT Shu Xiao-Ou XO Kang Daehee D Zheng Wei W

Nature genetics 20140720 8

In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene; P=8.82×10(-9)), rs10474352 at 5q14.3 (near the ARRDC3 gene; P=1.67×10(-9)) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P=4.25×10(-8)). We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P=0.030, 0.0 ...[more]

PMID: 25038754

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Project description:Background & aimsGenome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations.MethodsWe analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels.ResultsA meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci.ConclusionsWe showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.

Dataset Information

Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1.

Publications

Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1.

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