Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk.

Abstract

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.

• Authors: Zhiyu Xia, Yu-Ru Su, Paneen Petersen, Lihong Qi, Andre E Kim, Jane C Figueiredo, Yi Lin, Hongmei Nan, Lori C Sakoda, Demetrius Albanes, Sonja I Berndt, Stéphane Bézieau, Stephanie Bien, Daniel D Buchanan, Graham Casey, Andrew T Chan, David V Conti, David A Drew, Steven J Gallinger, W James Gauderman, Graham G Giles, Stephen B Gruber, Marc J Gunter, Michael Hoffmeister, Mark A Jenkins, Amit D Joshi, Loic Le Marchand, Juan P Lewinger, Li Li, Noralane M Lindor, Victor Moreno, Neil Murphy, Rami Nassir, Polly A Newcomb, Shuji Ogino, Gad Rennert, Mingyang Song, Xiaoliang Wang, Alicja Wolk, Michael O Woods, Hermann Brenner, Emily White, Martha L Slattery, Edward L Giovannucci, Jenny Chang-Claude, Paul D P Pharoah, Li Hsu, Peter T Campbell, Ulrike Peters
• Journal: Cancer medicine (Cancer Med) Vol. 9 Issue 10 Pg. 3563-3573 (05 2020) ISSN: 2045-7634 [Electronic] United States
• PMID: 32207560 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• CD33 protein, human
• FOXA1 protein, human
• Hepatocyte Nuclear Factor 3-alpha
• KIAA0753 protein, human
• Microtubule-Associated Proteins
• PSMC5 protein, human
• SCN1B protein, human
• Sialic Acid Binding Ig-like Lectin 3
• Voltage-Gated Sodium Channel beta-1 Subunit
• PTPN2 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 2
• Proteasome Endopeptidase Complex
• ATPases Associated with Diverse Cellular Activities

Topics

• ATPases Associated with Diverse Cellular Activities (genetics)
• Aged
• Body Mass Index
• Colorectal Neoplasms (epidemiology, genetics)
• Databases, Genetic
• Diabetes Mellitus, Type 2 (epidemiology)
• Female
• Gene Expression
• Genotype
• Hepatocyte Nuclear Factor 3-alpha (genetics)
• Humans
• Male
• Microtubule-Associated Proteins (genetics)
• Middle Aged
• Obesity (epidemiology)
• Phenotype
• Proteasome Endopeptidase Complex (genetics)
• Protein Tyrosine Phosphatase, Non-Receptor Type 2 (genetics)
• Sex Factors
• Sialic Acid Binding Ig-like Lectin 3 (genetics)
• Voltage-Gated Sodium Channel beta-1 Subunit (genetics)