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Hum Genet. 2019 Apr;138(4):307-326. doi: 10.1007/s00439-019-01989-8. Epub 2019 Feb 28.

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

Bien SA1,2, Su YR3,4, Conti DV5,6,4, Harrison TA3,4, Qu C3,4, Guo X7,4, Lu Y7,4, Albanes D8,4, Auer PL9,4, Banbury BL3,4, Berndt SI8,4, Bézieau S10,11,4, Brenner H12,13,14,4, Buchanan DD15,16,17,4, Caan BJ18,4, Campbell PT19,4, Carlson CS3,4, Chan AT20,21,4, Chang-Claude J22,23,4, Chen S24,4, Connolly CM3,4, Easton DF25,4, Feskens EJM26,4, Gallinger S27,4, Giles GG15,28,4, Gunter MJ29,4, Hampe J30,4, Huyghe JR3,4, Hoffmeister M12,4, Hudson TJ31,32,4, Jacobs EJ19,4, Jenkins MA15,4, Kampman E26,4, Kang HM24,4, Kühn T33,4, Küry S10,11,4, Lejbkowicz F34,35,4, Le Marchand L36,4, Milne RL15,28,4, Li L37,4, Li CI3,4, Lindblom A38,39,4, Lindor NM40,4, Martín V41,42,4, McNeil CE5,4, Melas M5,4, Moreno V42,43,44,4, Newcomb PA3,4, Offit K45,4, Pharaoh PDP46,4, Potter JD3,4, Qu C5,4, Riboli E47,4, Rennert G34,35,4, Sala N48,49,4, Schafmayer C50,4, Scacheri PC51,4, Schmit SL52,53,4, Severi G54,4, Slattery ML55,4, Smith JD56,4, Trichopoulou A57,58,4, Tumino R59,4, Ulrich CM60,4, van Duijnhoven FJB26,4, Van Guelpen B61,4, Weinstein SJ8,4, White E3,4, Wolk A62,63,4, Woods MO64,4, Wu AH5,6,4, Abecasis GR24,4, Casey G54,4, Nickerson DA56,4, Gruber SB5,4, Hsu L3,4, Zheng W7,4,65, Peters U3,4.

Author information

1
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. sbien@fredhutch.org.
2
Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA. sbien@fredhutch.org.
3
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
4
Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
5
USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
6
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
7
Division of Epidemiology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
8
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.
9
Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, 53205, USA.
10
Centre Hospitalier Universitaire Hotel-Dieu, 44093, Nantes, France.
11
Service de Génétique Médiczle, Centre Hospitalier Universitaire (CHU), 44093, Nantes, France.
12
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
13
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany.
14
German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
15
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3010, Australia.
16
Colorectal Oncogenomics Group, Department of Pathology, University of Melbourne, Melbourne, VIC, 3010, Australia.
17
Genetic Medicine and Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, VIC, 3010, Australia.
18
Division of Research, Kaiser Permanente Medical Care Program of Northern California, Oakland, CA, 94612, USA.
19
Epidemiology Research Program, American Cancer Society, Atlanta, GA, 30329-4251, USA.
20
Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
21
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
22
Unit of Genetic Epidemiology, Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
23
Genetic Tumour Epidemiology Group, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg, 20246, Hamburg, Germany.
24
Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA.
25
Department of Public Health and Primary Care School of Clinical Medicine, University of Cambridge, Cambridge, England, 01223, UK.
26
Division of Human Nutrition, Wageningen University & Research, Wageningen, The Netherlands.
27
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, 1X5, Canada.
28
Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, 3004, Australia.
29
Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.
30
Medical Department 1, University Hospital Dresden, TU Dresden, 01307, Dresden, Germany.
31
Ontario Institute for Cancer Research, Toronto, ON, Canada.
32
AbbVie Inc, 1500 Seaport Blvd, Redwood City, CA, 94063, USA.
33
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
34
Clalit Health Services National Israeli Cancer Control Center, 34361, Haifa, Israel.
35
Department of Community Medicine and Epidemiology, Carmel Medical Center, 34361, Haifa, Israel.
36
University of Hawai'i Cancer Center, Honolulu, Hawaii, 96813, USA.
37
Department of Family Medicine and Community Health, Case Western Reserve University, Cleveland, OH, 44106, USA.
38
Department of Clinical Genetics, Karolinska University Hospital Solna, 171 77, Stockholm, Sweden.
39
Department of Molecular Medicine and Surgery, Karolinska Institutet Solna, 171 77, Stockholm, Sweden.
40
Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, AZ, 85259, USA.
41
Biomedicine Institute (IBIOMED), University of León, León, Spain.
42
CIBER Epidemiología y Salud Pública (CIBERESP), 28029, Madrid, Spain.
43
Catalan Institute of Oncology, Bellvitge Biomedical Research Institute (IDIBELL), 08028, Barcelona, Spain.
44
University of Barcelona, 08007, Barcelona, Spain.
45
Department of Medicine, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
46
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, CB2 1TN, UK.
47
School of Public Health, Imperial College London, London, UK.
48
Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.
49
Molecular Epidemiology Group, Translational Research Laboratory, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.
50
Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, 24118, Kiel, Germany.
51
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
52
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Inc, Tampa, FL, 33612, USA.
53
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Inc, Tampa, FL, 33612, USA.
54
Centre for Research in Epidemiology and Population Health, Institut de Cancérologie Gustave Roussy, Villejuif, France.
55
Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
56
Department Genome Sciences, University of Washington, 98195, Seattle, WA, USA.
57
Hellenic Health Foundation, 13 Kaisareias & Alexandroupoleos, 115 27, Athens, Greece.
58
WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 115 27, Athens, Greece.
59
Affiliation Cancer Registry, Department of Prevention, Azienda Sanitaria Provinciale di Ragusa, Ragusa, Italy.
60
Population Sciences, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA.
61
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
62
Institute of Environmental Medicine, Karolinska Institutet Solna, 17177, Stockholm, Sweden.
63
Department of Surgical Sciences, Uppsala University, 75121, Uppsala, Sweden.
64
Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, Saint John's, NL, A1B 3V6, Canada.
65
Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, 37232, USA.

Abstract

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 FDR ≤ 0.2 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 = 2.2 × 10- 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10- 4, replication P = 6.7 × 10- 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.

PMID:
30820706
PMCID:
PMC6483948
DOI:
10.1007/s00439-019-01989-8
[Indexed for MEDLINE]
Free PMC Article

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