Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study

Ovarian Cancer Association Consortium, AOCS Group & Australian Cancer Study (Ovarian Cancer)

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

BACKGROUND: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC.

METHODS: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis.

RESULTS: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81).

CONCLUSIONS: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.

Original languageEnglish (US)
Pages (from-to)884-895
Number of pages12
JournalInternational Journal of Epidemiology
Volume45
Issue number3
DOIs
StatePublished - Jun 1 2016

Fingerprint

Random Allocation
Ovarian Neoplasms
Body Mass Index
Odds Ratio
Confidence Intervals
Observational Studies
Proxy
Genetic Markers
Single Nucleotide Polymorphism
Meta-Analysis
Weight Loss
Neoplasms
Logistic Models
Alleles

Keywords

  • Body mass index
  • Mendelian randomization analysis
  • obesity
  • ovarian neoplasms

ASJC Scopus subject areas

  • Epidemiology

Cite this

Ovarian Cancer Association Consortium, & AOCS Group & Australian Cancer Study (Ovarian Cancer) (2016). Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study. International Journal of Epidemiology, 45(3), 884-895. https://doi.org/10.1093/ije/dyw158

Adult body mass index and risk of ovarian cancer by subtype : a Mendelian randomization study. / Ovarian Cancer Association Consortium; AOCS Group & Australian Cancer Study (Ovarian Cancer).

In: International Journal of Epidemiology, Vol. 45, No. 3, 01.06.2016, p. 884-895.

Research output: Contribution to journalArticle

Ovarian Cancer Association Consortium & AOCS Group & Australian Cancer Study (Ovarian Cancer) 2016, 'Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study', International Journal of Epidemiology, vol. 45, no. 3, pp. 884-895. https://doi.org/10.1093/ije/dyw158
Ovarian Cancer Association Consortium, AOCS Group & Australian Cancer Study (Ovarian Cancer). Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study. International Journal of Epidemiology. 2016 Jun 1;45(3):884-895. https://doi.org/10.1093/ije/dyw158
Ovarian Cancer Association Consortium ; AOCS Group & Australian Cancer Study (Ovarian Cancer). / Adult body mass index and risk of ovarian cancer by subtype : a Mendelian randomization study. In: International Journal of Epidemiology. 2016 ; Vol. 45, No. 3. pp. 884-895.
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abstract = "BACKGROUND: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC.METHODS: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95{\%} confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis.RESULTS: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95{\%} CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95{\%} CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95{\%} CI 1.33-2.81).CONCLUSIONS: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.",
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TY - JOUR

T1 - Adult body mass index and risk of ovarian cancer by subtype

T2 - a Mendelian randomization study

AU - Ovarian Cancer Association Consortium

AU - AOCS Group & Australian Cancer Study (Ovarian Cancer)

AU - Dixon, Suzanne C.

AU - Nagle, Christina M.

AU - Thrift, Aaron P.

AU - Pharoah, Paul Dp

AU - Pearce, Celeste Leigh

AU - Zheng, Wei

AU - Painter, Jodie N.

AU - Chenevix-Trench, Georgia

AU - Fasching, Peter A.

AU - Beckmann, Matthias W.

AU - Lambrechts, Diether

AU - Vergote, Ignace

AU - Lambrechts, Sandrina

AU - Van Nieuwenhuysen, Els

AU - Rossing, Mary Anne

AU - Doherty, Jennifer A.

AU - Wicklund, Kristine G.

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Moysich, Kirsten B.

AU - Odunsi, Kunle

AU - Goodman, Marc T.

AU - Wilkens, Lynne R.

AU - Thompson, Pamela J.

AU - Shvetsov, Yurii B.

AU - Dörk, Thilo

AU - Park-Simon, Tjoung Won

AU - Hillemanns, Peter

AU - Bogdanova, Natalia

AU - Butzow, Ralf

AU - Nevanlinna, Heli

AU - Pelttari, Liisa M.

AU - Leminen, Arto

AU - Modugno, Francesmary

AU - Ness, Roberta B.

AU - Edwards, Robert P.

AU - Kelley, Joseph L.

AU - Heitz, Florian

AU - Karlan, Beth Y.

AU - Kjær, Susanne K.

AU - Høgdall, Estrid

AU - Jensen, Allan

AU - Goode, Ellen L

AU - Fridley, Brooke L.

AU - Cunningham, Julie M

AU - Winham, Stacey J

AU - Giles, Graham G.

AU - Bruinsma, Fiona

AU - Milne, Roger L.

AU - Southey, Melissa C.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - BACKGROUND: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC.METHODS: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis.RESULTS: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81).CONCLUSIONS: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.

AB - BACKGROUND: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC.METHODS: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis.RESULTS: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81).CONCLUSIONS: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.

KW - Body mass index

KW - Mendelian randomization analysis

KW - obesity

KW - ovarian neoplasms

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