British journal of cancer · 2022
Disentangling the aetiological pathways between body mass index and site-specific cancer risk using tissue-partitioned Mendelian randomisation.
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Leyden Genevieve M, Greenwood Michael P, Gaborieau Valérie, Han Younghun, Amos Christopher I, Brennan Paul, Murphy David, Davey Smith George, Richardson Tom G
Аннотация
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.
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.