Genetic correlation and causal relationships between cardio-metabolic traits and lung function impairment
Author(s)
Type
Journal Article
Abstract
Abstract
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
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
Date Issued
2021-06-21
Date Acceptance
2021-06-21
Citation
Genome Medicine, 2021, 13 (1), pp.1-13
ISSN
1756-994X
Publisher
BioMed Central
Start Page
1
End Page
13
Journal / Book Title
Genome Medicine
Volume
13
Issue
1
Copyright Statement
© 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 http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.
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 http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.
License URL
Identifier
https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-021-00914-x
Subjects
Obesity
Chronic obstructive lung disease
Matabolic syndrome
metabolic syndrome
UK Biobank
Publication Status
Published
Article Number
ARTN 104
Date Publish Online
2021-06-21