University of Oulu

Wielscher, M., Amaral, A.F.S., van der Plaat, D. et al. Genetic correlation and causal relationships between cardio-metabolic traits and lung function impairment. Genome Med 13, 104 (2021).

Genetic correlation and causal relationships between cardio-metabolic traits and lung function impairment

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Author: Wielscher, Matthias1; Amaral, Andre F. S.2; van der Plaat, Diana2;
Organizations: 1Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, UK
2National Heart and Lung Institute (NHLI), Imperial College London, Emmanuel Kaye Building, London, SW3 6LR, UK
3Genetic Epidemiology Group, Department of Health Sciences, George Davies Centre, University of Leicester, University Rd, Leicester, LE1 7RH, UK
4National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, University Rd, Leicester, LE1 7RH, UK
5Center for Life Course Health Research, Faculty of Medicine, University of Oulu, P.O.Box 8000, FI-90014, Oulu, Finland
6Biocenter of Oulu, University of Oulu, Aapistie 5, FI-90014, Oulu, Finland
7Research Unit of Biomedicine, Medical Research Center (MRC), University of Oulu, University Hospital, P.O. Box 8000, Oulu, Finland
8Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, 41 Jackowskiego St, 60-512, Poznan, Poland
9Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Kingston Lane, London, UB8 3PH, UK
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.7 MB)
Persistent link:
Language: English
Published: Springer Nature, 2021
Publish Date: 2021-10-26


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 Northern Finland Birth cohort 1966, (2) cross-trait linkage disequilibrium score regression (LDSC) to compare genetic backgrounds and (3) Mendelian randomisation (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 the UK Biobank data or published large-scale genome-wide association studies (N > 82,000).

Results: We observed a negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR), we found associations between type 2 diabetes (T2D) instruments and forced vital capacity (FVC) as well as FEV1/FVC. Body mass index (BMI) instruments were associated to all lung function traits and C-reactive protein (CRP) instruments to FVC. These genetic associations 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.

Conclusions: The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being attributed to inflammatory mechanisms. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.

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Series: Genome medicine
ISSN: 1756-994X
ISSN-E: 1756-994X
ISSN-L: 1756-994X
Volume: 13
Article number: 104
DOI: 10.1186/s13073-021-00914-x
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
3141 Health care science
Funding: 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). This research has been conducted using the UK Biobank Resource under Application Number 19136, and we thank the participants, field workers, and data managers for their time and cooperation. NFBC1966 received financial support from University of Oulu Grant no. 24000692, Oulu University Hospital Grant no. 24301140, ERDF European Regional Development Fund Grant no. 539/2010 A31592. L.V. Wain holds a GSK/British Lung Foundation Chair in Respiratory Research. The research was partially supported by the NIHR Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. SS and MRJ aknowledge the financial support from the European Union’s Horizon 2020 research and innovation programme 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. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
EU Grant Number: (633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(733206) LIFECYCLE - Early-life stressors and LifeCycle health
(824989) EUCAN-Connect - A federated FAIR platform enabling large-scale analysis of high-value cohort data connecting Europe and Canada in personalized health
(874739) LONGITOOLS - Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases
Copyright information: © The Author(s). 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit