Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer

被引：43

作者：

Bien, Stephanie A. ^{[1
,65
]}

Su, Yu-Ru ^{[1
,65
]}

Conti, David V. ^{[2
,3
,65
]}

Harrison, Tabitha A. ^{[1
,65
]}

Qu, Conghui ^{[1
,65
]}

Guo, Xingyi ^{[4
,65
]}

Lu, Yingchang ^{[4
,65
]}

Albanes, Demetrius ^{[5
,65
]}

Auer, Paul L. ^{[6
,65
]}

Banbury, Barbara L. ^{[1
,65
]}

Berndt, Sonja I. ^{[5
,65
]}

Bezieau, Stephane ^{[7
,8
,65
]}

Brenner, Hermann ^{[9
,10
,11
,12
,65
]}

Buchanan, Daniel D. ^{[13
,14
,15
,65
]}

Caan, Bette J. ^{[16
,65
]}

Campbell, Peter T. ^{[17
,65
]}

Carlson, Christopher S. ^{[1
,65
]}

Chan, Andrew T. ^{[18
,19
,20
,65
]}

Chang-Claude, Jenny ^{[21
,22
,65
]}

Chen, Sai ^{[23
,65
]}

Connolly, Charles M. ^{[1
,65
]}

Easton, Douglas F. ^{[24
,25
,65
]}

Feskens, Edith J. M. ^{[26
,65
]}

Gallinger, Steven ^{[27
,65
]}

Giles, Graham G. ^{[13
,28
,65
]}

Gunter, Marc J. ^{[29
,65
]}

Hampe, Jochen ^{[30
,65
]}

Huyghe, Jeroen R. ^{[1
,65
]}

Hoffmeister, Michael ^{[9
,65
]}

Hudson, Thomas J. ^{[31
,32
,65
]}

Jacobs, Eric J. ^{[17
,65
]}

Jenkins, Mark A. ^{[13
,65
]}

Kampman, Ellen ^{[26
,65
]}

Kang, Hyun Min ^{[23
,65
]}

Kuehn, Tilman ^{[33
,65
]}

Kury, Sebastien ^{[7
,8
,65
]}

Lejbkowicz, Flavio ^{[34
,35
,65
]}

Le Marchand, Loic ^{[36
,65
]}

Milne, Roger L. ^{[13
,28
,65
]}

Li, Li ^{[37
,65
]}

Li, Christopher I. ^{[1
,65
]}

Lindblom, Annika ^{[38
,39
,65
]}

Lindor, Noralane M. ^{[40
,65
]}

Martin, Vicente ^{[41
,42
,65
]}

McNeil, Caroline E. ^{[2
,65
]}

Melas, Marilena ^{[2
,65
]}

Moreno, Victor ^{[42
,43
,44
,65
]}

Newcomb, Polly A. ^{[1
,65
]}

Offit, Kenneth ^{[45
,65
]}

Pharaoh, Paul D. P. ^{[46
,65
]}

机构：

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

[2] Univ Southern Calif, USC Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA

[3] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA

[4] Vanderbilt Univ, Sch Med, Div Epidemiol, Nashville, TN 37232 USA

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

[6] Univ Wisconsin, Joseph J Zilber Sch Publ Hlth, Milwaukee, WI 53205 USA

[7] CHU Hotel Dieu, F-44093 Nantes, France

[8] CHU Nantes, Serv Genet Med, F-44093 Nantes, France

[9] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany

[10] German Canc Res Ctr, Div Prevent Oncol, D-69120 Heidelberg, Germany

[11] Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany

[12] German Canc Consortium DKTK, D-69120 Heidelberg, Germany

[13] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Parkville, Vic 3010, Australia

[14] Univ Melbourne, Dept Pathol, Colorectal Oncogen Grp, Melbourne, Vic 3010, Australia

[15] Royal Melbourne Hosp, Genet Med & Familial Canc Ctr, Parkville, Vic 3010, Australia

[16] Kaiser Permanente Med Care Program Northern Calif, Div Res, Oakland, CA 94612 USA

[17] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA

[18] Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA

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

[20] Harvard Med Sch, Boston, MA 02115 USA

[21] German Canc Res Ctr, Div Canc Epidemiol, Unit Genet Epidemiol, D-69120 Heidelberg, Germany

[22] Univ Canc Ctr Hamburg, Univ Med Ctr Hamburg, Genet Tumour Epidemiol Grp, D-20246 Hamburg, Germany

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

[24] Univ Cambridge, Dept Publ Hlth, Cambridge, England

[25] Univ Cambridge, Primary Care Sch Clin Med, Cambridge, England

[26] Wageningen Univ & Res, Div Human Nutr, Wageningen, Netherlands

[27] Univ Toronto, Lunenfeld Tanenbaum Res Inst, Mt Sinai Hosp, Toronto, ON ON 1X5, Canada

[28] Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic 3004, Australia

[29] Aarhus Univ, Sect Epidemiol, Dept Publ Hlth, Aarhus, Denmark

[30] Univ Hosp Dresden, Med Dept 1, TU Dresden, D-01307 Dresden, Germany

[31] Ontario Inst Canc Res, Toronto, ON, Canada

[32] AbbVie Inc, 1500 Seaport Blvd, Redwood City, CA 94063 USA

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

[34] Natl Israeli Canc Control Ctr, Clalit Hlth Serv, IL-34361 Haifa, Israel

[35] Carmel Hosp, Dept Community Med & Epidemiol, IL-34361 Haifa, Israel

[36] Univ Hawaii, Canc Ctr, Honolulu, HI 96813 USA

[37] Case Western Reserve Univ, Dept Family Med & Community Hlth, Cleveland, OH 44106 USA

[38] Karolinska Univ, Hosp Solna, Dept Clin Genet, S-17177 Stockholm, Sweden

[39] Karolinska Inst Solna, Dept Mol Med & Surg, S-17177 Stockholm, Sweden

[40] Mayo Clin Arizona, Dept Hlth Sci Res, Scottsdale, AZ 85259 USA

[41] Univ Leon, Biomed Inst IBIOMED, Leon, Spain

[42] CIBER Epidemiol & Salud Publ CIBERESP, Madrid 28029, Spain

[43] Bellvitge Biomed Res Inst IDIBELL, Catalan Inst Oncol, Barcelona 08028, Spain

[44] Univ Barcelona, E-08007 Barcelona, Spain

[45] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, Dept Med, New York, NY 10065 USA

[46] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge CB2 1TN, England

[47] Imperial Coll London, Sch Publ Hlth, London, England

[48] Catalan Inst Oncol IDIBELL, Canc Epidemiol Res Program, Unit Nutr & Canc, Barcelona 08908, Spain

[49] Catalan Inst Oncol IDIBELL, Mol Epidemiol Grp, Translat Res Lab, Barcelona 08908, Spain

[50] Univ Hosp Schleswig Holstein, Dept Gen & Thorac Surg, Campus Kiel, D-24118 Kiel, Germany

来源：

HUMAN GENETICS | 2019年 / 138卷 / 04期

基金：

英国医学研究理事会; 瑞典研究理事会; 美国国家卫生研究院; 澳大利亚国家健康与医学研究理事会; 加拿大健康研究院;

关键词：

GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; HYDROGEN-PEROXIDE; GLYCOGEN-PHOSPHORYLASE; GENOTYPE IMPUTATION; TRIPARTITE MOTIF; IDENTIFICATION; COLON; METAANALYSIS; CELLS;

D O I：

10.1007/s00439-019-01989-8

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n=169) and whole blood (n=922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P=2.2x10(-4), replication P=0.01), and PYGL (discovery P=2.3x10(-4), replication P=6.7x10(-4)). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P<0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.

引用

页码：307 / 326

页数：20

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