Discovery of common and rare genetic risk variants for colorectal cancer

被引：377

作者：

Huyghe, Jeroen R. ^{[1
]}

Bien, Stephanie A. ^{[1
]}

Harrison, Tabitha A. ^{[1
]}

Kang, Hyun Min ^{[2
,3
]}

Chen, Sai ^{[2
,3
]}

Schmit, Stephanie L. ^{[4
]}

Conti, David V. ^{[5
]}

Qu, Conghui ^{[1
]}

Jeon, Jihyoun ^{[6
]}

Edlund, Christopher K. ^{[5
]}

Greenside, Peyton ^{[7
]}

Wainberg, Michael ^{[8
]}

Schumacher, Fredrick R. ^{[9
]}

Smith, Joshua D. ^{[10
]}

Levine, David M. ^{[11
]}

Nelson, Sarah C. ^{[11
]}

Sinnott-Armstrong, Nasa A. ^{[12
]}

Albanes, Demetrius ^{[13
]}

Alonso, M. Henar ^{[14
,15
,16
]}

Anderson, Kristin ^{[17
]}

Arnau-Collell, Coral ^{[18
]}

Arndt, Volker ^{[19
]}

Bamia, Christina ^{[20
,21
]}

Banbury, Barbara L. ^{[1
]}

Baron, John A. ^{[22
]}

Berndt, Sonja I. ^{[13
]}

Bezieau, Stephane ^{[23
]}

Bishop, D. Timothy ^{[24
]}

Boehm, Juergen ^{[25
,26
]}

Boeing, Heiner ^{[27
]}

Brenner, Hermann ^{[19
,28
,29
,30
]}

Brezina, Stefanie ^{[31
]}

Buch, Stephan ^{[32
]}

Buchanan, Daniel D. ^{[33
,34
,35
]}

Burnett-Hartman, Andrea ^{[36
]}

Butterbach, Katja ^{[19
]}

Caan, Bette J. ^{[37
]}

Campbell, Peter T. ^{[38
]}

Carlson, Christopher S. ^{[1
,39
]}

Castellvi-Bel, Sergi ^{[18
]}

Chan, Andrew T. ^{[40
,41
,42
,43
,44
,45
,46
]}

Chang-Claude, Jenny ^{[47
,48
]}

Chanock, Stephen J. ^{[13
]}

Chirlaque, Maria-Dolores ^{[15
,49
]}

Cho, Sang Hee ^{[50
]}

Connolly, Charles M. ^{[1
]}

Cross, Amanda J. ^{[51
,52
]}

Cuk, Katarina ^{[19
]}

Curtis, Keith R. ^{[1
]}

de la Chapelle, Albert ^{[53
,54
]}

机构：

[1] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA

[2] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[4] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA

[5] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA

[6] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA

[7] Stanford Univ, Biomed Informat Program, Stanford, CA 94305 USA

[8] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA

[9] Case Western Reserve Univ, Dept Populat & Quantitat Hlth Sci, Cleveland, OH 44106 USA

[10] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[11] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[12] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[13] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA

[14] Catalan Inst Oncol IDIBELL, Canc Prevent & Control Program, Barcelona, Spain

[15] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain

[16] Univ Barcelona, Dept Clin Sci, Fac Med, Barcelona, Spain

[17] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA

[18] Univ Barcelona, Dept Gastroenterol, Hosp Clin, Inst Invest Biomed August Pi & Sunyer IDIBAPS,Ctr, Barcelona, Spain

[19] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany

[20] Hellen Hlth Fdn, Athens, Greece

[21] Natl & Kapodistrian Univ Athens, WHO Collaborating Ctr Nutr & Hlth, Unit Nutr Epidemiol & Nutr Publ Hlth, Dept Hyg Epidemiol & Med Stat,Sch Med, Athens, Greece

[22] Univ N Carolina, Dept Med, Sch Med, Chapel Hill, NC 27515 USA

[23] Ctr Hosp Univ CHU Nantes, Serv Genet Med, Nantes, France

[24] St Jamess Univ Leeds, Leeds Inst Med Res, Leeds, W Yorkshire, England

[25] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA

[26] Univ Utah, Dept Populat Hlth Sci, Salt Lake City, UT USA

[27] German Inst Human Nutr Potsdam Rehbrucke, Dept Epidemiol, Potsdam, Germany

[28] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany

[29] Natl Ctr Tumor Dis NCT, Heidelberg, Germany

[30] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany

[31] Med Univ Vienna, Inst Canc Res, Dept Med 1, Vienna, Austria

[32] Tech Univ Dresden, Dept Med 1, Univ Hosp Dresden, Dresden, Germany

[33] Univ Melbourne, Colorectal Oncogen Grp, Dept Clin Pathol, Parkville, Vic, Australia

[34] Univ Melbourne, Ctr Canc Res, Victorian Comprehens Canc Ctr, Parkville, Vic, Australia

[35] Royal Melbourne Hosp, Genom Med & Family Canc Clin, Parkville, Vic, Australia

[36] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA

[37] Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA

[38] Amer Canc Soc, Behav & Epidemiol Res Grp, Atlanta, GA 30329 USA

[39] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[40] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA

[41] Harvard Med Sch, Boston, MA 02114 USA

[42] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA

[43] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA

[44] Broad Inst Harvard & MIT, Cambridge, MA USA

[45] Harvard Univ, Dept Epidemiol, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA

[46] Harvard Univ, Dept Immunol & Infect Dis, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA

[47] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[48] UCCH, Canc Epidemiol Grp, Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany

[49] Murcia Univ, Dept Epidemiol, Reg Hlth Council, IMIB Arrixaca, Murcia, Spain

[50] Chonnam Natl Univ Hosp, Dept Hematol Oncol, Hwasun, South Korea

来源：

NATURE GENETICS | 2019年 / 51卷 / 01期

关键词：

GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; COLON-CANCER; LYSOPHOSPHATIDIC ACID; QUALITY-CONTROL; IDENTIFIES; 6; ORGAN SIZE; METAANALYSIS; EXPRESSION; MUTATIONS;

D O I：

10.1038/s41588-018-0286-6

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

引用

页码：76 / +

页数：15

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