Genetic risk score mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer

Jodie N. Painter; Tracy A. O'Mara; Louise Marquart; Penelope M. Webb; John Attia; Sarah E. Medland; Timothy Cheng; Joe Dennis; Elizabeth G. Holliday; Mark McEvoy; Rodney J. Scott; Shahana Ahmed; Catherine S. Healey; Mitul Shah; Maggie Gorman; Lynn Martin; Shirley V. Hodgson; Matthias W. Beckmann; Arif B. Ekici; Peter A. Fasching; Alexander Hein; Matthias Rübner; Kamila Czene; Hatef Darabi; Per Hall; Jingmei Li; Thilo Dörk; Matthias Dürst; Peter Hillemanns; Ingo B. Runnebaum; Frederic Amant; Daniela Annibali; Jeroen Depreeuw; Diether Lambrechts; Patrick Neven; Julie M. Cunningham; Sean C. Dowdy; Ellen L. Goode; Brooke L. Fridley; Stacey J. Winham; Tormund S. Njølstad; Helga B. Salvesen; Jone Trovik; Henrica M.J. Werner; Katie A. Ashton; Geoffrey Otton; Anthony Proietto; Miriam Mints; Emma Tham; Manjeet K. Bolla; Kyriaki Michailidou; Qin Wang; Jonathan P. Tyrer; John L. Hopper; Julian Peto; Anthony J. Swerdlow; Barbara Burwinkel; Hermann Brenner; Alfons Meindl; Hiltrud Brauch; Annika Lindblom; Jenny Chang-Claude; Fergus J. Couch; Graham G. Giles; Vessela N. Kristensen; Angela Cox; Paul D.P. Pharoah; Ian Tomlinson; Alison M. Dunning; Douglas F. Easton; Deborah J. Thompson; Amanda B. Spurdle

doi:10.1158/1055-9965.EPI-16-0147

Genetic risk score mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer

Jodie N. Painter, Tracy A. O'Mara, Louise Marquart, Penelope M. Webb, John Attia, Sarah E. Medland, Timothy Cheng, Joe Dennis, Elizabeth G. Holliday, Mark McEvoy, Rodney J. Scott, Shahana Ahmed, Catherine S. Healey, Mitul Shah, Maggie Gorman, Lynn Martin, Shirley V. Hodgson, Matthias W. Beckmann, Arif B. Ekici, Peter A. FaschingAlexander Hein, Matthias Rübner, Kamila Czene, Hatef Darabi, Per Hall, Jingmei Li, Thilo Dörk, Matthias Dürst, Peter Hillemanns, Ingo B. Runnebaum, Frederic Amant, Daniela Annibali, Jeroen Depreeuw, Diether Lambrechts, Patrick Neven, Julie M. Cunningham, Sean C. Dowdy, Ellen L. Goode, Brooke L. Fridley, Stacey J. Winham, Tormund S. Njølstad, Helga B. Salvesen, Jone Trovik, Henrica M.J. Werner, Katie A. Ashton, Geoffrey Otton, Anthony Proietto, Miriam Mints, Emma Tham, Manjeet K. Bolla, Kyriaki Michailidou, Qin Wang, Jonathan P. Tyrer, John L. Hopper, Julian Peto, Anthony J. Swerdlow, Barbara Burwinkel, Hermann Brenner, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Jenny Chang-Claude, Fergus J. Couch, Graham G. Giles, Vessela N. Kristensen, Angela Cox, Paul D.P. Pharoah, Ian Tomlinson, Alison M. Dunning, Douglas F. Easton, Deborah J. Thompson, Amanda B. Spurdle

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26 Scopus citations

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 metaanalysis were used to test for associations between endometrial cancer risk and (i) individual BMI orWHRSNPs, (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 < 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.

Original language	English (US)
Pages (from-to)	1503-1510
Number of pages	8
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	25
Issue number	11
DOIs	https://doi.org/10.1158/1055-9965.EPI-16-0147
State	Published - Nov 1 2016

ASJC Scopus subject areas

General Medicine

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10.1158/1055-9965.EPI-16-0147

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Painter, J. N., O'Mara, T. A., Marquart, L., Webb, P. M., Attia, J., Medland, S. E., Cheng, T., Dennis, J., Holliday, E. G., McEvoy, M., Scott, R. J., Ahmed, S., Healey, C. S., Shah, M., Gorman, M., Martin, L., Hodgson, S. V., Beckmann, M. W., Ekici, A. B., ... Spurdle, A. B. (2016). Genetic risk score mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer. Cancer Epidemiology Biomarkers and Prevention, 25(11), 1503-1510. https://doi.org/10.1158/1055-9965.EPI-16-0147

Genetic risk score mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer. / Painter, Jodie N.; O'Mara, Tracy A.; Marquart, Louise et al.
In: Cancer Epidemiology Biomarkers and Prevention, Vol. 25, No. 11, 01.11.2016, p. 1503-1510.

Research output: Contribution to journal › Article › peer-review

Painter, JN, O'Mara, TA, Marquart, L, Webb, PM, Attia, J, Medland, SE, Cheng, T, Dennis, J, Holliday, EG, McEvoy, M, Scott, RJ, Ahmed, S, Healey, CS, Shah, M, Gorman, M, Martin, L, Hodgson, SV, Beckmann, MW, Ekici, AB, Fasching, PA, Hein, A, Rübner, M, Czene, K, Darabi, H, Hall, P, Li, J, Dörk, T, Dürst, M, Hillemanns, P, Runnebaum, IB, Amant, F, Annibali, D, Depreeuw, J, Lambrechts, D, Neven, P, Cunningham, JM , Dowdy, SC , Goode, EL, Fridley, BL, Winham, SJ, Njølstad, TS, Salvesen, HB, Trovik, J, Werner, HMJ, Ashton, KA, Otton, G, Proietto, A, Mints, M, Tham, E, Bolla, MK, Michailidou, K, Wang, Q, Tyrer, JP, Hopper, JL, Peto, J, Swerdlow, AJ, Burwinkel, B, Brenner, H, Meindl, A, Brauch, H, Lindblom, A, Chang-Claude, J, Couch, FJ, Giles, GG, Kristensen, VN, Cox, A, Pharoah, PDP, Tomlinson, I, Dunning, AM, Easton, DF, Thompson, DJ & Spurdle, AB 2016, 'Genetic risk score mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer', Cancer Epidemiology Biomarkers and Prevention, vol. 25, no. 11, pp. 1503-1510. https://doi.org/10.1158/1055-9965.EPI-16-0147

@article{8357b3a5ae1c44e79962bb9560498e96,

title = "Genetic risk score mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer",

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 metaanalysis were used to test for associations between endometrial cancer risk and (i) individual BMI orWHRSNPs, (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 < 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.",

author = "Painter, {Jodie N.} and O'Mara, {Tracy A.} and Louise Marquart and Webb, {Penelope M.} and John Attia and Medland, {Sarah E.} and Timothy Cheng and Joe Dennis and Holliday, {Elizabeth G.} and Mark McEvoy and Scott, {Rodney J.} and Shahana Ahmed and Healey, {Catherine S.} and Mitul Shah and Maggie Gorman and Lynn Martin and Hodgson, {Shirley V.} and Beckmann, {Matthias W.} and Ekici, {Arif B.} and Fasching, {Peter A.} and Alexander Hein and Matthias R{\"u}bner and Kamila Czene and Hatef Darabi and Per Hall and Jingmei Li and Thilo D{\"o}rk and Matthias D{\"u}rst and Peter Hillemanns and Runnebaum, {Ingo B.} and Frederic Amant and Daniela Annibali and Jeroen Depreeuw and Diether Lambrechts and Patrick Neven and Cunningham, {Julie M.} and Dowdy, {Sean C.} and Goode, {Ellen L.} and Fridley, {Brooke L.} and Winham, {Stacey J.} and Nj{\o}lstad, {Tormund S.} and Salvesen, {Helga B.} and Jone Trovik and Werner, {Henrica M.J.} and Ashton, {Katie A.} and Geoffrey Otton and Anthony Proietto and Miriam Mints and Emma Tham and Bolla, {Manjeet K.} and Kyriaki Michailidou and Qin Wang and Tyrer, {Jonathan P.} and Hopper, {John L.} and Julian Peto and Swerdlow, {Anthony J.} and Barbara Burwinkel and Hermann Brenner and Alfons Meindl and Hiltrud Brauch and Annika Lindblom and Jenny Chang-Claude and Couch, {Fergus J.} and Giles, {Graham G.} and Kristensen, {Vessela N.} and Angela Cox and Pharoah, {Paul D.P.} and Ian Tomlinson and Dunning, {Alison M.} and Easton, {Douglas F.} and Thompson, {Deborah J.} and Spurdle, {Amanda B.}",

note = "Funding Information: ANECS recruitment was supported by project grants from the NHMRC (ID#339435), The Cancer Council Queensland (ID# 4196615), and Cancer Council Tasmania (ID#403031 and ID#457636). SEARCH recruitment was funded by a programme grant fromCancer ResearchUK (C490/A10124)",

year = "2016",

month = nov,

day = "1",

doi = "10.1158/1055-9965.EPI-16-0147",

language = "English (US)",

volume = "25",

pages = "1503--1510",

journal = "Cancer Epidemiology Biomarkers and Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research Inc.",

number = "11",

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TY - JOUR

T1 - Genetic risk score mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer

AU - Painter, Jodie N.

AU - O'Mara, Tracy A.

AU - Marquart, Louise

AU - Webb, Penelope M.

AU - Attia, John

AU - Medland, Sarah E.

AU - Cheng, Timothy

AU - Dennis, Joe

AU - Holliday, Elizabeth G.

AU - McEvoy, Mark

AU - Scott, Rodney J.

AU - Ahmed, Shahana

AU - Healey, Catherine S.

AU - Shah, Mitul

AU - Gorman, Maggie

AU - Martin, Lynn

AU - Hodgson, Shirley V.

AU - Beckmann, Matthias W.

AU - Ekici, Arif B.

AU - Fasching, Peter A.

AU - Hein, Alexander

AU - Rübner, Matthias

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Hall, Per

AU - Li, Jingmei

AU - Dörk, Thilo

AU - Dürst, Matthias

AU - Hillemanns, Peter

AU - Runnebaum, Ingo B.

AU - Amant, Frederic

AU - Annibali, Daniela

AU - Depreeuw, Jeroen

AU - Lambrechts, Diether

AU - Neven, Patrick

AU - Cunningham, Julie M.

AU - Dowdy, Sean C.

AU - Goode, Ellen L.

AU - Fridley, Brooke L.

AU - Winham, Stacey J.

AU - Njølstad, Tormund S.

AU - Salvesen, Helga B.

AU - Trovik, Jone

AU - Werner, Henrica M.J.

AU - Ashton, Katie A.

AU - Otton, Geoffrey

AU - Proietto, Anthony

AU - Mints, Miriam

AU - Tham, Emma

AU - Bolla, Manjeet K.

AU - Michailidou, Kyriaki

AU - Wang, Qin

AU - Tyrer, Jonathan P.

AU - Hopper, John L.

AU - Peto, Julian

AU - Swerdlow, Anthony J.

AU - Burwinkel, Barbara

AU - Brenner, Hermann

AU - Meindl, Alfons

AU - Brauch, Hiltrud

AU - Lindblom, Annika

AU - Chang-Claude, Jenny

AU - Couch, Fergus J.

AU - Giles, Graham G.

AU - Kristensen, Vessela N.

AU - Cox, Angela

AU - Pharoah, Paul D.P.

AU - Tomlinson, Ian

AU - Dunning, Alison M.

AU - Easton, Douglas F.

AU - Thompson, Deborah J.

AU - Spurdle, Amanda B.

N1 - Funding Information: ANECS recruitment was supported by project grants from the NHMRC (ID#339435), The Cancer Council Queensland (ID# 4196615), and Cancer Council Tasmania (ID#403031 and ID#457636). SEARCH recruitment was funded by a programme grant fromCancer ResearchUK (C490/A10124)

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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 metaanalysis were used to test for associations between endometrial cancer risk and (i) individual BMI orWHRSNPs, (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 < 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.

AB - 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 metaanalysis were used to test for associations between endometrial cancer risk and (i) individual BMI orWHRSNPs, (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 < 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.

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SN - 1055-9965

VL - 25

SP - 1503

EP - 1510

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

IS - 11

ER -

Genetic risk score mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer

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