Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.
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ICR Authors
Authors
Chen, Z
Guo, X
Tao, R
Huyghe, JR
Law, PJ
Fernandez-Rozadilla, C
Ping, J
Jia, G
Long, J
Li, C
Shen, Q
Xie, Y
Timofeeva, MN
Thomas, M
Schmit, SL
Díez-Obrero, V
Devall, M
Moratalla-Navarro, F
Fernandez-Tajes, J
Palles, C
Sherwood, K
Briggs, SEW
Svinti, V
Donnelly, K
Farrington, SM
Blackmur, J
Vaughan-Shaw, PG
Shu, X-O
Lu, Y
Broderick, P
Studd, J
Harrison, TA
Conti, DV
Schumacher, FR
Melas, M
Rennert, G
Obón-Santacana, M
Martín-Sánchez, V
Oh, JH
Kim, J
Jee, SH
Jung, KJ
Kweon, S-S
Shin, M-H
Shin, A
Ahn, Y-O
Kim, D-H
Oze, I
Wen, W
Matsuo, K
Matsuda, K
Tanikawa, C
Ren, Z
Gao, Y-T
Jia, W-H
Hopper, JL
Jenkins, MA
Win, AK
Pai, RK
Figueiredo, JC
Haile, RW
Gallinger, S
Woods, MO
Newcomb, PA
Duggan, D
Cheadle, JP
Kaplan, R
Kerr, R
Kerr, D
Kirac, I
Böhm, J
Mecklin, J-P
Jousilahti, P
Knekt, P
Aaltonen, LA
Rissanen, H
Pukkala, E
Eriksson, JG
Cajuso, T
Hänninen, U
Kondelin, J
Palin, K
Tanskanen, T
Renkonen-Sinisalo, L
Männistö, S
Albanes, D
Weinstein, SJ
Ruiz-Narvaez, E
Palmer, JR
Buchanan, DD
Platz, EA
Visvanathan, K
Ulrich, CM
Siegel, E
Brezina, S
Gsur, A
Campbell, PT
Chang-Claude, J
Hoffmeister, M
Brenner, H
Slattery, ML
Potter, JD
Tsilidis, KK
Schulze, MB
Gunter, MJ
Murphy, N
Castells, A
Castellví-Bel, S
Moreira, L
Arndt, V
Shcherbina, A
Bishop, DT
Giles, GG
Southey, MC
Idos, GE
McDonnell, KJ
Abu-Ful, Z
Greenson, JK
Shulman, K
Lejbkowicz, F
Offit, K
Su, Y-R
Steinfelder, R
Keku, TO
van Guelpen, B
Hudson, TJ
Hampel, H
Pearlman, R
Berndt, SI
Hayes, RB
Martinez, ME
Thomas, SS
Pharoah, PDP
Larsson, SC
Yen, Y
Lenz, H-J
White, E
Li, L
Doheny, KF
Pugh, E
Shelford, T
Chan, AT
Cruz-Correa, M
Lindblom, A
Hunter, DJ
Joshi, AD
Schafmayer, C
Scacheri, PC
Kundaje, A
Schoen, RE
Hampe, J
Stadler, ZK
Vodicka, P
Vodickova, L
Vymetalkova, V
Edlund, CK
Gauderman, WJ
Shibata, D
Toland, A
Markowitz, S
Kim, A
Chanock, SJ
van Duijnhoven, F
Feskens, EJM
Sakoda, LC
Gago-Dominguez, M
Wolk, A
Pardini, B
FitzGerald, LM
Lee, SC
Ogino, S
Bien, SA
Kooperberg, C
Li, CI
Lin, Y
Prentice, R
Qu, C
Bézieau, S
Yamaji, T
Sawada, N
Iwasaki, M
Le Marchand, L
Wu, AH
Qu, C
McNeil, CE
Coetzee, G
Hayward, C
Deary, IJ
Harris, SE
Theodoratou, E
Reid, S
Walker, M
Ooi, LY
Lau, KS
Zhao, H
Hsu, L
Cai, Q
Dunlop, MG
Gruber, SB
Houlston, RS
Moreno, V
Casey, G
Peters, U
Tomlinson, I
Zheng, W
Guo, X
Tao, R
Huyghe, JR
Law, PJ
Fernandez-Rozadilla, C
Ping, J
Jia, G
Long, J
Li, C
Shen, Q
Xie, Y
Timofeeva, MN
Thomas, M
Schmit, SL
Díez-Obrero, V
Devall, M
Moratalla-Navarro, F
Fernandez-Tajes, J
Palles, C
Sherwood, K
Briggs, SEW
Svinti, V
Donnelly, K
Farrington, SM
Blackmur, J
Vaughan-Shaw, PG
Shu, X-O
Lu, Y
Broderick, P
Studd, J
Harrison, TA
Conti, DV
Schumacher, FR
Melas, M
Rennert, G
Obón-Santacana, M
Martín-Sánchez, V
Oh, JH
Kim, J
Jee, SH
Jung, KJ
Kweon, S-S
Shin, M-H
Shin, A
Ahn, Y-O
Kim, D-H
Oze, I
Wen, W
Matsuo, K
Matsuda, K
Tanikawa, C
Ren, Z
Gao, Y-T
Jia, W-H
Hopper, JL
Jenkins, MA
Win, AK
Pai, RK
Figueiredo, JC
Haile, RW
Gallinger, S
Woods, MO
Newcomb, PA
Duggan, D
Cheadle, JP
Kaplan, R
Kerr, R
Kerr, D
Kirac, I
Böhm, J
Mecklin, J-P
Jousilahti, P
Knekt, P
Aaltonen, LA
Rissanen, H
Pukkala, E
Eriksson, JG
Cajuso, T
Hänninen, U
Kondelin, J
Palin, K
Tanskanen, T
Renkonen-Sinisalo, L
Männistö, S
Albanes, D
Weinstein, SJ
Ruiz-Narvaez, E
Palmer, JR
Buchanan, DD
Platz, EA
Visvanathan, K
Ulrich, CM
Siegel, E
Brezina, S
Gsur, A
Campbell, PT
Chang-Claude, J
Hoffmeister, M
Brenner, H
Slattery, ML
Potter, JD
Tsilidis, KK
Schulze, MB
Gunter, MJ
Murphy, N
Castells, A
Castellví-Bel, S
Moreira, L
Arndt, V
Shcherbina, A
Bishop, DT
Giles, GG
Southey, MC
Idos, GE
McDonnell, KJ
Abu-Ful, Z
Greenson, JK
Shulman, K
Lejbkowicz, F
Offit, K
Su, Y-R
Steinfelder, R
Keku, TO
van Guelpen, B
Hudson, TJ
Hampel, H
Pearlman, R
Berndt, SI
Hayes, RB
Martinez, ME
Thomas, SS
Pharoah, PDP
Larsson, SC
Yen, Y
Lenz, H-J
White, E
Li, L
Doheny, KF
Pugh, E
Shelford, T
Chan, AT
Cruz-Correa, M
Lindblom, A
Hunter, DJ
Joshi, AD
Schafmayer, C
Scacheri, PC
Kundaje, A
Schoen, RE
Hampe, J
Stadler, ZK
Vodicka, P
Vodickova, L
Vymetalkova, V
Edlund, CK
Gauderman, WJ
Shibata, D
Toland, A
Markowitz, S
Kim, A
Chanock, SJ
van Duijnhoven, F
Feskens, EJM
Sakoda, LC
Gago-Dominguez, M
Wolk, A
Pardini, B
FitzGerald, LM
Lee, SC
Ogino, S
Bien, SA
Kooperberg, C
Li, CI
Lin, Y
Prentice, R
Qu, C
Bézieau, S
Yamaji, T
Sawada, N
Iwasaki, M
Le Marchand, L
Wu, AH
Qu, C
McNeil, CE
Coetzee, G
Hayward, C
Deary, IJ
Harris, SE
Theodoratou, E
Reid, S
Walker, M
Ooi, LY
Lau, KS
Zhao, H
Hsu, L
Cai, Q
Dunlop, MG
Gruber, SB
Houlston, RS
Moreno, V
Casey, G
Peters, U
Tomlinson, I
Zheng, W
Document Type
Journal Article
Date
2024-04-26
Date Accepted
2024-03-26
Abstract
Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
Citation
Nature Communications, 2024, 15 (1), pp. 3557 -
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
2041-1723
2041-1723
Collections
Research Team
Cancer Genomics