Cardiovascular disease and subsequent risk of psychiatric disorders: a nationwide sibling-controlled study
Abstract
Background: The association between cardiovascular disease (CVD) and selected psychiatric disorders has frequently been suggested while the potential role of familial factors and comorbidities in such association has rarely been investigated.
Methods: We identified 869 056 patients newly diagnosed with CVD from 1987 to 2016 in Sweden with no history of psychiatric disorders, and 910 178 full siblings of these patients as well as 10 individually age- and sex-matched unrelated population controls (N=8 690 560). Adjusting for multiple comorbid conditions, we used flexible parametric models and Cox models to estimate the association of CVD with risk of all subsequent psychiatric disorders, comparing rates of first incident psychiatric disorder among CVD patients with rates among unaffected full siblings and population controls.
Results: The median age at diagnosis was 60 years for patients with CVD and 59.2% were male. During up to thirty years of follow-up, the crude incidence rates of psychiatric disorder were 7.1, 4.6 and 4.0 per 1000 person-years for patients with CVD, their siblings and population controls. In the sibling comparison, we observed an increased risk of psychiatric disorder during the first year after CVD diagnosis (hazard ratio [HR], 2.74; 95% confidence interval [CI], 2.62-2.87) and thereafter (1.45; 95% CI, 1.42-1.48). Increased risks were observed for all types of psychiatric disorders and among all diagnoses of CVD. We observed similar associations in the population comparison. CVD patients who developed a comorbid psychiatric disorder during the first year after diagnosis were at elevated risk of subsequent CVD death compared to patients without such comorbidity (HR 1.55; 95% CI 1.44-1.67).
Conclusions: Patients diagnosed with CVD are at an elevated risk for subsequent psychiatric disorders independent of shared familial factors and comorbid conditions. Comorbid psychiatric disorders in patients with CVD are associated with higher risk of cardiovascular mortality suggesting that surveillance and treatment of psychiatric comorbidities should be considered as an integral part of clinical management of newly diagnosed CVD patients.
Funding: This work was supported by the EU Horizon 2020 Research and Innovation Action Grant (CoMorMent, grant no. 847776 to UV, PFS and FF), Grant of Excellence, Icelandic Research Fund (grant no. 163362-051 to UV), ERC Consolidator Grant (StressGene, grant no: 726413 to UV), Swedish Research Council (grant no. D0886501 to PFS) and US NIMH R01 MH123724 (to PFS).
Data availability
Data analyses were performed in STATA 17.0 (StataCorp LP). STATA script used in the primary analyses has been made available as supplementary appendix. Aggregated data used for generating figures are available in supplementary appendix. The original data used in this study are owned by the Swedish National Board of Health and Welfare and Statistics Sweden. The authors are not able to make the dataset publicly available according to the Public Access to Information and Secrecy Act in Sweden. Any researchers (including international researchers) interested in accessing the data can send request to the authorities for data application by: 1) apply for ethical approval from local ethical review board; 2) contact the Swedish National Board of Health and Welfare (https://bestalladata.socialstyrelsen.se/, email: registerservice@socialstyrelsen.se) and/or Statistics Sweden (https://www.scb.se/vara-tjanster/bestall-data-och-statistik/, email: scb@scb.se) with the ethical approval and submit a formal application for access to register data. The same contacts can be used for detailed information about how to apply for access to register data for research purposes."
Article and author information
Author details
Funding
EU Horizon 2020 Research and Innovation Action Grant (CoMorMent,847776)
- Unnur Valdimarsdóttir
EU Horizon 2020 Research and Innovation Action Grant (CoMorMent,847776)
- Fang Fang
EU Horizon 2020 Research and Innovation Action Grant (CoMorMent,847776)
- Patrick Sullivan
Grant of Excellence, Icelandic Research Fund (163362-51)
- Unnur Valdimarsdóttir
ERC Consolidator Grant (StressGene,726413)
- Unnur Valdimarsdóttir
Swedish Research Council (D0886501)
- Patrick Sullivan
US NIMH R01 (MH123724)
- Patrick Sullivan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The study was approved by the Ethical Vetting Board in Stockholm, Sweden (DNRs 2012/1814-31/4 and 2015/1062-32). Informed consent to each participant was waived by Swedish law in nationwide registry data.
Reviewing Editor
- Prabhat Jha, University of Toronto, Canada
Publication history
- Received: May 10, 2022
- Preprint posted: June 27, 2022 (view preprint)
- Accepted: October 20, 2022
- Accepted Manuscript published: October 21, 2022 (version 1)
- Version of Record published: December 2, 2022 (version 2)
Copyright
© 2022, Shen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Background: While biological age in adults is often understood as representing general health and resilience, the conceptual interpretation of accelerated biological age in children and its relationship to development remains unclear. We aimed to clarify the relationship of accelerated biological age, assessed through two established biological age indicators, telomere length and DNA methylation age, and two novel candidate biological age indicators , to child developmental outcomes, including growth and adiposity, cognition, behaviour, lung function and onset of puberty, among European school-age children participating in the HELIX exposome cohort.
Methods: The study population included up to 1,173 children, aged between 5 and 12 years, from study centres in the UK, France, Spain, Norway, Lithuania, and Greece. Telomere length was measured through qPCR, blood DNA methylation and gene expression was measured using microarray, and proteins and metabolites were measured by a range of targeted assays. DNA methylation age was assessed using Horvath's skin and blood clock, while novel blood transcriptome and 'immunometabolic' (based on plasma protein and urinary and serum metabolite data) clocks were derived and tested in a subset of children assessed six months after the main follow-up visit. Associations between biological age indicators with child developmental measures as well as health risk factors were estimated using linear regression, adjusted for chronological age, sex, ethnicity and study centre. The clock derived markers were expressed as Δ age (i.e., predicted minus chronological age).
Results: Transcriptome and immunometabolic clocks predicted chronological age well in the test set (r= 0.93 and r= 0.84 respectively). Generally, weak correlations were observed, after adjustment for chronological age, between the biological age indicators. Among associations with health risk factors, higher birthweight was associated with greater immunometabolic Δ age, smoke exposure with greater DNA methylation Δ age and high family affluence with longer telomere length. Among associations with child developmental measures, all biological age markers were associated with greater BMI and fat mass, and all markers except telomere length were associated with greater height, at least at nominal significance (p<0.05). Immunometabolic Δ age was associated with better working memory (p = 4e -3) and reduced inattentiveness (p= 4e -4), while DNA methylation Δ age was associated with greater inattentiveness (p=0.03) and poorer externalizing behaviours (p= 0.01). Shorter telomere length was also associated with poorer externalizing behaviours (p=0.03).
Conclusions: In children, as in adults, biological ageing appears to be a multi-faceted process and adiposity is an important correlate of accelerated biological ageing. Patterns of associations suggested that accelerated immunometabolic age may be beneficial for some aspects of child development while accelerated DNA methylation age and telomere attrition may reflect early detrimental aspects of biological ageing, apparent even in children.
Funding: UK Research and Innovation (MR/S03532X/1); European Commission (grant agreement numbers: 308333; 874583).