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. 2016 Jun;45(3):896-908.
doi: 10.1093/ije/dyw129. Epub 2016 Jul 17.

Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer

Chi Gao  1 , Chirag J Patel  2 , Kyriaki Michailidou  3 , Ulrike Peters  4 , Jian Gong  4 , Joellen Schildkraut  5 , Fredrick R Schumacher  6 , Wei Zheng  7 , Paolo Boffetta  8 , Isabelle Stucker  9 , Walter Willett  10 , Stephen Gruber  11 , Douglas F Easton  12 , David J Hunter  13 , Thomas A Sellers  14 , Christopher Haiman  6 , Brian E Henderson  6 , Rayjean J Hung  15 , Christopher Amos  16 , Brandon L Pierce  17 , Sara Lindström  1 , Peter Kraft; the Colorectal Transdisciplinary Study (CORECT); Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE); Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE); Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI); and Transdisciplinary Research in Cancer of the Lung (TRICL)
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Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer

Chi Gao et al. Int J Epidemiol. 2016 Jun.

Abstract

Background: Adiposity traits have been associated with risk of many cancers in observational studies, but whether these associations are causal is unclear. Mendelian randomization (MR) uses genetic predictors of risk factors as instrumental variables to eliminate reverse causation and reduce confounding bias. We performed MR analyses to assess the possible causal relationship of birthweight, childhood and adult body mass index (BMI), and waist-hip ratio (WHR) on the risks of breast, ovarian, prostate, colorectal and lung cancers.

Methods: We tested the association between genetic risk scores and each trait using summary statistics from published genome-wide association studies (GWAS) and from 51 537 cancer cases and 61 600 controls in the Genetic Associations and Mechanisms in Oncology (GAME-ON) Consortium.

Results: We found an inverse association between the genetic score for childhood BMI and risk of breast cancer [odds ratio (OR) = 0.71 per standard deviation (s.d.) increase in childhood BMI; 95% confidence interval (CI): 0.60, 0.80; P = 6.5 × 10(-5)). We also found the genetic score for adult BMI to be inversely associated with breast cancer risk (OR = 0.66 per s.d. increase in BMI; 95% CI: 0.57, 0.77; P = 2.5 × 10(-7)), and positively associated with ovarian cancer (OR = 1.35; 95% CI: 1.05, 1.72; P = 0.017), lung cancer (OR = 1.27; 95% CI: 1.09, 1.49; P = 2.9 × 10(-3)) and colorectal cancer (OR = 1.39; 95% CI: 1.06, 1.82, P = 0.016). The inverse association between genetically predicted adult BMI and breast cancer risk remained even after adjusting for directional pleiotropy via MR-Egger regression.

Conclusions: Findings from this study provide additional understandings of the complex relationship between adiposity and cancer risks. Our results for breast and lung cancer are particularly interesting, given previous reports of effect heterogeneity by menopausal status and smoking status.

Keywords: Cancer risk; Mendelian randomization; body mass index; post-GWAS study; waist-to-hip ratio.

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Figures

Figure 1.
Figure 1.
Scatterplot of SNP-specific effects for the associations with adult BMI and a) breast cancer(top left), b) ovarian cancer risk(top right), c) colorectal cancer(bottom left), d) lung cancer(bottom right) for all 77 BMI-associated SNPs. SNP-specific vertical and horizontal bars correspond to standard errors for the breast/ovarian/colorectal/lung cancer association and BMI association respectively. The shaded region corresponds to 95%CI of the association between BMI and cancer risk.
Figure 2.
Figure 2.
DAG demonstrating one potential explanation of how genetic variants influence postmenopausal breast cancer risk.
See this image and copyright information in PMC

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