Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk
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Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk. / Xia, Zhiyu; Su, Yu-Ru; Petersen, Paneen; Qi, Lihong; Kim, Andre E; Figueiredo, Jane C; Lin, Yi; Nan, Hongmei; Sakoda, Lori C; Albanes, Demetrius; Berndt, Sonja I; Bézieau, Stéphane; Bien, Stephanie; Buchanan, Daniel D; Casey, Graham; Chan, Andrew T; Conti, David V; Drew, David A; Gallinger, Steven J; Gauderman, W James; Giles, Graham G; Gruber, Stephen B; Gunter, Marc J; Hoffmeister, Michael; Jenkins, Mark A; Joshi, Amit D; Le Marchand, Loic; Lewinger, Juan P; Li, Li; Lindor, Noralane M; Moreno, Victor; Murphy, Neil; Nassir, Rami; Newcomb, Polly A; Ogino, Shuji; Rennert, Gad; Song, Mingyang; Wang, Xiaoliang; Wolk, Alicja; Woods, Michael O; Brenner, Hermann; White, Emily; Slattery, Martha L; Giovannucci, Edward L; Chang-Claude, Jenny; Pharoah, Paul D P; Hsu, Li; Campbell, Peter T.
In: CANCER MED-US, Vol. 9, No. 10, 05.2020, p. 3563-3573.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk
AU - Xia, Zhiyu
AU - Su, Yu-Ru
AU - Petersen, Paneen
AU - Qi, Lihong
AU - Kim, Andre E
AU - Figueiredo, Jane C
AU - Lin, Yi
AU - Nan, Hongmei
AU - Sakoda, Lori C
AU - Albanes, Demetrius
AU - Berndt, Sonja I
AU - Bézieau, Stéphane
AU - Bien, Stephanie
AU - Buchanan, Daniel D
AU - Casey, Graham
AU - Chan, Andrew T
AU - Conti, David V
AU - Drew, David A
AU - Gallinger, Steven J
AU - Gauderman, W James
AU - Giles, Graham G
AU - Gruber, Stephen B
AU - Gunter, Marc J
AU - Hoffmeister, Michael
AU - Jenkins, Mark A
AU - Joshi, Amit D
AU - Le Marchand, Loic
AU - Lewinger, Juan P
AU - Li, Li
AU - Lindor, Noralane M
AU - Moreno, Victor
AU - Murphy, Neil
AU - Nassir, Rami
AU - Newcomb, Polly A
AU - Ogino, Shuji
AU - Rennert, Gad
AU - Song, Mingyang
AU - Wang, Xiaoliang
AU - Wolk, Alicja
AU - Woods, Michael O
AU - Brenner, Hermann
AU - White, Emily
AU - Slattery, Martha L
AU - Giovannucci, Edward L
AU - Chang-Claude, Jenny
AU - Pharoah, Paul D P
AU - Hsu, Li
AU - Campbell, Peter T
N1 - © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
PY - 2020/5
Y1 - 2020/5
N2 - BACKGROUND: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology.METHODS: To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2 ) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2.RESULTS: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10-5 ), PSMC5 (P = 4.51 × 10-4 ) and CD33 (P = 2.71 × 10-4 ) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10-5 ) and SCN1B (P = 2.76 × 10-4 ) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10-5 ).CONCLUSIONS: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.
AB - BACKGROUND: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology.METHODS: To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2 ) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2.RESULTS: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10-5 ), PSMC5 (P = 4.51 × 10-4 ) and CD33 (P = 2.71 × 10-4 ) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10-5 ) and SCN1B (P = 2.76 × 10-4 ) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10-5 ).CONCLUSIONS: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.
U2 - 10.1002/cam4.2971
DO - 10.1002/cam4.2971
M3 - SCORING: Journal article
C2 - 32207560
VL - 9
SP - 3563
EP - 3573
JO - CANCER MED-US
JF - CANCER MED-US
SN - 2045-7634
IS - 10
ER -