Disentangling the aetiological pathways between body mass index and site-specific cancer risk using tissue-partitioned Mendelian randomisation

Genevieve Leyden; Michael P Greenwood; Valerie Gaborieau; Younghun Han; Christopher I. Amos; Paul Brennan; David Murphy; George Davey Smith; Tom G Richardson

doi:10.1038/s41416-022-02060-6

Disentangling the aetiological pathways between body mass index and site-specific cancer risk using tissue-partitioned Mendelian randomisation

Genevieve Leyden^*
, Michael P Greenwood
, Valerie Gaborieau
, Younghun Han
, Christopher I. Amos
, Paul Brennan
, David Murphy
, George Davey Smith
, Tom G Richardson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

8 Citations (Scopus)

104 Downloads (Pure)

Abstract

Background
Body mass index (BMI) is known to influence the risk of various site-specific cancers, however, dissecting which subcomponents of this heterogenous risk factor are predominantly responsible for driving disease effects has proven difficult to establish. We have leveraged tissue-specific gene expression to separate the effects of distinct phenotypes underlying BMI on the risk of seven site-specific cancers.

Methods
SNP-exposure estimates were weighted in a multivariable Mendelian randomisation analysis by their evidence for colocalization with subcutaneous adipose- and brain-tissue-derived gene expression using a recently developed methodology.

Results
Our results provide evidence that brain-tissue-derived BMI variants are predominantly responsible for driving the genetically predicted effect of BMI on lung cancer (OR: 1.17; 95% CI: 1.01–1.36; P = 0.03). Similar findings were identified when analysing cigarettes per day as an outcome (Beta = 0.44; 95% CI: 0.26–0.61; P = 1.62 × 10−6), highlighting a possible shared aetiology or mediator effect between brain-tissue BMI, smoking and lung cancer. Our results additionally suggest that adipose-tissue-derived BMI variants may predominantly drive the effect of BMI and increased risk for endometrial cancer (OR: 1.71; 95% CI: 1.07–2.74; P = 0.02), highlighting a putatively important role in the aetiology of endometrial cancer.

Conclusions
The study provides valuable insight into the divergent underlying pathways between BMI and the risk of site-specific cancers.

Original language	English
Number of pages	8
Journal	British Journal of Cancer
DOIs	https://doi.org/10.1038/s41416-022-02060-6
Publication status	Published - 24 Nov 2022

Bibliographical note

Funding Information:
GML is supported by a grant from the British Heart Foundation (FS/17/60/33474). This work was supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). The funder had no role in the study design, analysis or interpretation of data; the funder had no role in the manuscript or the decision to submit the study for publication.

Publisher Copyright:
© 2022, The Author(s).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Groups and Themes

Bristol Population Health Science Institute

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

An exploration of genetic paradigms to investigate neuroregulatory genetic pathways in cardiovascular health
Leyden, G. M. (Author), Murphy, D. (Supervisor), Richardson, T. G. (Supervisor) & Greenwood, M. P. (Supervisor), 9 May 2023
Student thesis: Doctoral Thesis › Doctor of Philosophy (PhD)

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Cite this

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title = "Disentangling the aetiological pathways between body mass index and site-specific cancer risk using tissue-partitioned Mendelian randomisation",

abstract = "Background Body mass index (BMI) is known to influence the risk of various site-specific cancers, however, dissecting which subcomponents of this heterogenous risk factor are predominantly responsible for driving disease effects has proven difficult to establish. We have leveraged tissue-specific gene expression to separate the effects of distinct phenotypes underlying BMI on the risk of seven site-specific cancers. Methods SNP-exposure estimates were weighted in a multivariable Mendelian randomisation analysis by their evidence for colocalization with subcutaneous adipose- and brain-tissue-derived gene expression using a recently developed methodology. Results Our results provide evidence that brain-tissue-derived BMI variants are predominantly responsible for driving the genetically predicted effect of BMI on lung cancer (OR: 1.17; 95\% CI: 1.01–1.36; P = 0.03). Similar findings were identified when analysing cigarettes per day as an outcome (Beta = 0.44; 95\% CI: 0.26–0.61; P = 1.62 × 10−6), highlighting a possible shared aetiology or mediator effect between brain-tissue BMI, smoking and lung cancer. Our results additionally suggest that adipose-tissue-derived BMI variants may predominantly drive the effect of BMI and increased risk for endometrial cancer (OR: 1.71; 95\% CI: 1.07–2.74; P = 0.02), highlighting a putatively important role in the aetiology of endometrial cancer. Conclusions The study provides valuable insight into the divergent underlying pathways between BMI and the risk of site-specific cancers.",

author = "Genevieve Leyden and Greenwood, \{Michael P\} and Valerie Gaborieau and Younghun Han and Amos, \{Christopher I.\} and Paul Brennan and David Murphy and \{Davey Smith\}, George and Richardson, \{Tom G\}",

note = "Funding Information: GML is supported by a grant from the British Heart Foundation (FS/17/60/33474). This work was supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC\_UU\_00011/1). The funder had no role in the study design, analysis or interpretation of data; the funder had no role in the manuscript or the decision to submit the study for publication. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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T1 - Disentangling the aetiological pathways between body mass index and site-specific cancer risk using tissue-partitioned Mendelian randomisation

AU - Leyden, Genevieve

AU - Greenwood, Michael P

AU - Gaborieau, Valerie

AU - Han, Younghun

AU - Amos, Christopher I.

AU - Brennan, Paul

AU - Murphy, David

AU - Davey Smith, George

AU - Richardson, Tom G

N1 - Funding Information: GML is supported by a grant from the British Heart Foundation (FS/17/60/33474). This work was supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). The funder had no role in the study design, analysis or interpretation of data; the funder had no role in the manuscript or the decision to submit the study for publication. Publisher Copyright: © 2022, The Author(s).

PY - 2022/11/24

Y1 - 2022/11/24

N2 - Background Body mass index (BMI) is known to influence the risk of various site-specific cancers, however, dissecting which subcomponents of this heterogenous risk factor are predominantly responsible for driving disease effects has proven difficult to establish. We have leveraged tissue-specific gene expression to separate the effects of distinct phenotypes underlying BMI on the risk of seven site-specific cancers. Methods SNP-exposure estimates were weighted in a multivariable Mendelian randomisation analysis by their evidence for colocalization with subcutaneous adipose- and brain-tissue-derived gene expression using a recently developed methodology. Results Our results provide evidence that brain-tissue-derived BMI variants are predominantly responsible for driving the genetically predicted effect of BMI on lung cancer (OR: 1.17; 95% CI: 1.01–1.36; P = 0.03). Similar findings were identified when analysing cigarettes per day as an outcome (Beta = 0.44; 95% CI: 0.26–0.61; P = 1.62 × 10−6), highlighting a possible shared aetiology or mediator effect between brain-tissue BMI, smoking and lung cancer. Our results additionally suggest that adipose-tissue-derived BMI variants may predominantly drive the effect of BMI and increased risk for endometrial cancer (OR: 1.71; 95% CI: 1.07–2.74; P = 0.02), highlighting a putatively important role in the aetiology of endometrial cancer. Conclusions The study provides valuable insight into the divergent underlying pathways between BMI and the risk of site-specific cancers.

AB - Background Body mass index (BMI) is known to influence the risk of various site-specific cancers, however, dissecting which subcomponents of this heterogenous risk factor are predominantly responsible for driving disease effects has proven difficult to establish. We have leveraged tissue-specific gene expression to separate the effects of distinct phenotypes underlying BMI on the risk of seven site-specific cancers. Methods SNP-exposure estimates were weighted in a multivariable Mendelian randomisation analysis by their evidence for colocalization with subcutaneous adipose- and brain-tissue-derived gene expression using a recently developed methodology. Results Our results provide evidence that brain-tissue-derived BMI variants are predominantly responsible for driving the genetically predicted effect of BMI on lung cancer (OR: 1.17; 95% CI: 1.01–1.36; P = 0.03). Similar findings were identified when analysing cigarettes per day as an outcome (Beta = 0.44; 95% CI: 0.26–0.61; P = 1.62 × 10−6), highlighting a possible shared aetiology or mediator effect between brain-tissue BMI, smoking and lung cancer. Our results additionally suggest that adipose-tissue-derived BMI variants may predominantly drive the effect of BMI and increased risk for endometrial cancer (OR: 1.71; 95% CI: 1.07–2.74; P = 0.02), highlighting a putatively important role in the aetiology of endometrial cancer. Conclusions The study provides valuable insight into the divergent underlying pathways between BMI and the risk of site-specific cancers.

U2 - 10.1038/s41416-022-02060-6

DO - 10.1038/s41416-022-02060-6

M3 - Article (Academic Journal)

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SN - 0007-0920

JO - British Journal of Cancer

JF - British Journal of Cancer

ER -

Disentangling the aetiological pathways between body mass index and site-specific cancer risk using tissue-partitioned Mendelian randomisation

Abstract

Bibliographical note

UN SDGs

Research Groups and Themes

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Projects

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Student theses

An exploration of genetic paradigms to investigate neuroregulatory genetic pathways in cardiovascular health

Cite this