TY - JOUR
T1 - Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer
AU - Lu, Yingchang
AU - Kweon, Sun Seog
AU - Tanikawa, Chizu
AU - Jia, Wei Hua
AU - Xiang, Yong Bing
AU - Cai, Qiuyin
AU - Zeng, Chenjie
AU - Schmit, Stephanie L.
AU - Shin, Aesun
AU - Matsuo, Keitaro
AU - Jee, Sun Ha
AU - Kim, Dong Hyun
AU - Kim, Jeongseon
AU - Wen, Wanqing
AU - Shi, Jiajun
AU - Guo, Xingyi
AU - Li, Bingshan
AU - Wang, Nan
AU - Zhang, Ben
AU - Li, Xinxiang
AU - Shin, Min Ho
AU - Li, Hong Lan
AU - Ren, Zefang
AU - Oh, Jae Hwan
AU - Oze, Isao
AU - Ahn, Yoon Ok
AU - Jung, Keum Ji
AU - Conti, David V.
AU - Schumacher, Fredrick R.
AU - Rennert, Gad
AU - Jenkins, Mark A.
AU - Campbell, Peter T.
AU - Hoffmeister, Michael
AU - Casey, Graham
AU - Gruber, Stephen B.
AU - Gao, Jing
AU - Gao, Yu Tang
AU - Pan, Zhi Zhong
AU - Kamatani, Yoichiro
AU - Zeng, Yi Xin
AU - Shu, Xiao Ou
AU - Long, Jirong
AU - Matsuda, Koichi
AU - Zheng, Wei
N1 - Publisher Copyright:
© 2019 AGA Institute
PY - 2019/4
Y1 - 2019/4
N2 - Background & Aims: Genome-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. Methods: We 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. Results: A 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. Conclusions: We 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.
AB - Background & Aims: Genome-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. Methods: We 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. Results: A 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. Conclusions: We 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.
KW - Colon Cancer
KW - Epidemiology
KW - Genetic Variants
KW - Immunology
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U2 - 10.1053/j.gastro.2018.11.066
DO - 10.1053/j.gastro.2018.11.066
M3 - Article
C2 - 30529582
AN - SCOPUS:85063365207
SN - 0016-5085
VL - 156
SP - 1455
EP - 1466
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -