Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer
Authors: Painter Jodie N. , O'Mara Tracy A. , Marquart Louise , Webb Penelope M. , Attia John , Medland Sarah E. , Cheng Timothy , Dennis Joe , Holliday Elizabeth G. , McEvoy Mark , Scott Rodney J. , Ahmed Shahana , Healey Catherine S. , Shah Mitul , Gorman Maggie , Martin Lynn , Hodgson Shirley V. , Beckmann Matthias W. , Ekici Arif B. , Fasching Peter A. , Hein Alexander , Rübner Matthias , Czene Kamila , Darabi Hatef , Hall Per , Li Jingmei , Dörk Thilo , Dürst Matthias , Hillemanns Peter , Runnebaum Ingo B. , Amant Frederic , Annibali Daniela , Depreeuw Jeroen , Lambrechts Diether , Neven Patrick , Cunningham Julie M. , Dowdy Sean C. , Goode Ellen L. , Fridley Brooke L. , Winham Stacey J. , Njølstad Tormund S. , Salvesen Helga B. , Trovik Jone , Werner Henrica M.J. , Ashton Katie A. , Otton Geoffrey , Proietto Anthony , Mints Miriam , Tham Emma , Bolla Manjeet K. , Michailidou Kyriaki , Wang Qin , Tyrer Jonathan P. , Hopper John L. , Peto Julian , Swerdlow Anthony J. , Burwinkel Barbara , Brenner Hermann , Meindl Alfons , Brauch Hiltrud , Lindblom Annika , Chang-Claude Jenny , Couch Fergus J. , Giles Graham G. , Kristensen Vessela N. , Cox Angela , Pharoah Paul D.P. , Tomlinson Ian , Dunning Alison M. , Easton Douglas F. , Thompson Deborah J. , Spurdle Amanda B. 
Published: August 2016

Abstract
Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls.
Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable.
Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10–1.39; P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P &lt; 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS.
Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI.
Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503–10. ©2016 AACR.