Genetic Correlation and Causal Relationships between Cardio-Metabolic Traits and Lung Function Impairment

Background: Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors. Methods: We performed three analyses: 1) cardio-metabolic health to lung function association tests in NFBC1966, 2) cross trait LD score regression to compare genetic backgrounds and 3) Mendelian Randomization (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from UK Biobank data or published large-scale genome-wide association studies (N > 82,000). Findings: We observed negative genetic correlation between lung function and cardio-metabolic traits and diseases. We found associations between Type 2 Diabetes instruments and FVC as well as FEV1/FVC, BMI instruments on all lung function traits and CRP instruments on FVC. These genetic association provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure. Interpretation: Our findings support an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being mediated by CRP. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Funding Statement: This work was conducted within the Ageing Lungs in European Cohorts study funded through the European Union H2020 research and innovation programme (grant agreement number 633212). L.V. Wain was supported by the NIHR Leicester Biomedical Research Centre. SS and MRJ aknowledge financial support from: the European Union’s Horizon 2020 research and innovation program for the DynaHEALTH (under grant agreement No 633595), LifeCycle (under grant agreement No 733206), EUCANCONNECT (under grant agreement No 824989), LongITools (under grant agreement No 873749), and the JPI HDHL, PREcisE project, ZonMw the Netherlands no. P75416. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Missing.