TY  - JOUR
AU  - Bien, Stephanie A
AU  - Su, Yu-Ru
AU  - Conti, David V
AU  - Harrison, Tabitha A
AU  - Qu, Conghui
AU  - Guo, Xingyi
AU  - Lu, Yingchang
AU  - Albanes, Demetrius
AU  - Auer, Paul L
AU  - Banbury, Barbara L
AU  - Berndt, Sonja I
AU  - Bézieau, Stéphane
AU  - Brenner, Hermann
AU  - Buchanan, Daniel D
AU  - Caan, Bette J
AU  - Campbell, Peter T
AU  - Carlson, Christopher S
AU  - Chan, Andrew T
AU  - Chang-Claude, Jenny
AU  - Chen, Sai
AU  - Connolly, Charles M
AU  - Easton, Douglas F
AU  - Feskens, Edith J M
AU  - Gallinger, Steven
AU  - Giles, Graham G
AU  - Gunter, Marc J
AU  - Hampe, Jochen
AU  - Huyghe, Jeroen R
AU  - Hoffmeister, Michael
AU  - Hudson, Thomas J
AU  - Jacobs, Eric J
AU  - Jenkins, Mark A
AU  - Kampman, Ellen
AU  - Kang, Hyun Min
AU  - Kühn, Tilman
AU  - Küry, Sébastien
AU  - Lejbkowicz, Flavio
AU  - Le Marchand, Loic
AU  - Milne, Roger L
AU  - Li, Li
AU  - Li, Christopher I
AU  - Lindblom, Annika
AU  - Lindor, Noralane M
AU  - Martín, Vicente
AU  - McNeil, Caroline E
AU  - Melas, Marilena
AU  - Moreno, Victor
AU  - Newcomb, Polly A
AU  - Offit, Kenneth
AU  - Pharaoh, Paul D P
AU  - Potter, John D
AU  - Qu, Chenxu
AU  - Riboli, Elio
AU  - Rennert, Gad
AU  - Sala, Núria
AU  - Schafmayer, Clemens
AU  - Scacheri, Peter C
AU  - Schmit, Stephanie L
AU  - Severi, Gianluca
AU  - Slattery, Martha L
AU  - Smith, Joshua D
AU  - Trichopoulou, Antonia
AU  - Tumino, Rosario
AU  - Ulrich, Cornelia M
AU  - van Duijnhoven, Fränzel J B
AU  - Van Guelpen, Bethany
AU  - Weinstein, Stephanie J
AU  - White, Emily
AU  - Wolk, Alicja
AU  - Woods, Michael O
AU  - Wu, Anna H
AU  - Abecasis, Goncalo R
AU  - Casey, Graham
AU  - Nickerson, Deborah A
AU  - Gruber, Stephen B
AU  - Hsu, Li
AU  - Zheng, Wei
AU  - Peters, Ulrike
TI  - Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer.
JO  - Human genetics 
VL  - 138
IS  - 4
SN  - 1432-1203
CY  - Heidelberg
PB  - Springer
M1  - DKFZ-2019-00632
SP  - 307-326
PY  - 2019
N1  - 138(4):307-326
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:30820706
DO  - DOI:10.1007/s00439-019-01989-8
UR  - https://inrepo02.dkfz.de/record/143007
ER  -