Genetic risk for schizophrenia is associated with changes in heart structure and function

The lifespan of individuals diagnosed with schizophrenia is estimated to be 20 years less than that of the general population (Laursen TM et al. 2014). Contributing to this reduced life expectancy are physical health conditions such as cardiovascular disease (Ringen PA et al. 2022). Although environmental factors like diet, exercise, medication, and smoking are likely involved, a genetic link between schizophrenia and risk factors for cardiovascular disease has also been found (Andreassen OA et al. 2013).

There is growing evidence of a genetic overlap between schizophrenia and factors known to be related to cardiovascular disease. Schizophrenia has been shown to share genetic components with triglycerides, lipoproteins, and body mass index (BMI), among other cardiovascular disease risk factors (Andreassen OA et al. 2013).

Moreover, a recent study used Mendelian Randomization (MR), a form of analysis that makes use of the random assortment of genes (see this recent blog post for more information on MR: Crick D, 2023), to establish a causal role for schizophrenia in increasing the risk of heart failure (Veeneman RR et al. 2022). Still, there is much to learn about the genetic basis of the observed co-occurrence of schizophrenia and cardiovascular dysfunction.

Toby Pillinger et al. (2023) recently published an article exploring whether genetic factors contribute to the relationship between schizophrenia and cardiac structure and function. The authors found that genetic risk for schizophrenia predicted magnetic resonance imaging (MRI)-derived features of cardiac structure and function in a population sample.

Schizophrenia has been shown to increase one’s risk of heart failure and this may in part be due to genetics.

Methods

The study by Pillinger et al. (2023) was conducted using data from the UK Biobank, a large, longitudinal, population study with information on a wide range of mental and physical characteristics including cardiac imaging and genetics.

Participants with a schizophrenia diagnosis were excluded. This allowed genetic risk of schizophrenia and cardiac measures to be assessed in a large general sample of individuals who did not already have a diagnosis of schizophrenia.

Machine learning was used to extract 13 structural and functional cardiac features, like stroke volumes and maximal end-diastolic septal wall thickness. In addition, genetic risk for schizophrenia was calculated both across the genome and using known specific genetic pathways for inflammation, transforming Growth Factor (TGF)-β, and myocardial fibrosis.

Results

With data from a total of 32,279 participants, Pillinger and colleagues discovered that greater genetic risk for schizophrenia was associated with structural and functional changes to the heart, such as greater ejection fractions and myocardial stiffness as well as decreased cardiac volume. Removal of participants taking antipsychotics did not alter these findings.

The authors also found that:

• A greater TGF-β-specific genetic risk score for schizophrenia was related to greater left ventricular end systolic volume and reduced left ventricular ejection fraction. Interestingly, these associations had an opposing direction of effect to the overall schizophrenia polygenic score. These opposing results highlight a need for greater investigation to help explain the true nature of the potential TGF-β mediated associations.

• The acute inflammation-specific genetic risk score for schizophrenia was somewhat associated with reduced longitudinal peak diastolic strain rates.

• There were no associations between the myocardial fibrosis-specific genetic risk score for schizophrenia and the cardiac features examined.

While these results suggest that TGF-β and inflammation may play a role in the association between schizophrenia and cardiac outcomes, these associations were weak and further research into how these effects take place (i.e., a mechanistic investigation) is needed.

Genetic risk for schizophrenia is related to structural and functional changes in the heart that can worsen cardiac outcomes.

Conclusions

Altogether, these findings provide support for a genetic link between schizophrenia and cardiac structure and function. Most associations suggest genetic liability to schizophrenia is associated with worse cardiac outcomes. These results provide further evidence for co-morbid risk of cardiovascular disease but further investigation within groups of patients with schizophrenia is required.

Future research should focus on how genetic risk for schizophrenia may increase risk of cardiovascular events in people with a diagnosis of schizophrenia.

Strengths and limitations

This study is a novel investigation of genetic risk for schizophrenia and cardiac structure and function. The authors used MRI-derived heart measures that have not previously been shown to be related to the genetic risk of schizophrenia. This provides some insight into potential mechanisms linking schizophrenia to cardiovascular disease.

However, the implications of these findings are limited by the small amount of schizophrenia heritability that is explained by its genetic risk score (~15%) (Trubetskoy V et al. 2022). Moreover, while Pillinger et al. use a common method to calculate genetic risk for schizophrenia, there have been recent approaches which have shown better prediction accuracy (Ni G et al. 2021). The use of pathway-specific genetic scores is an intriguing approach towards exploring potential biological mechanisms. The results of these analyses were limited but do provide some evidence for the involvement of inflammatory pathways in mediating the association between schizophrenia genetic risk and variation in heart-related outcomes.

Finally, the genetic makeup of schizophrenia is highly overlapping with many other psychiatric disorders (Hindley G et al. 2022). This raises the issue of specificity of the study results, meaning that it’s possible that similar findings would result from using a genetic risk score for other disorders, such as bipolar disorder or depression.

Overall, the study provides important support for a link between genetic risk of schizophrenia and cardiac features, but more effort is needed to improve the usability and determine whether these results are specific to the genetic risk of schizophrenia.

Many genes associated with schizophrenia have also been linked to other psychiatric disorders, like bipolar disorder and depression. So, changes in heart structure and function may not be unique to genetic risk for schizophrenia alone.

Implications for practice

There is still a long way to go before genetic risk scores can be used in psychiatric clinical practice. This study does suggest that genes play a role in the relationship between schizophrenia and cardiovascular dysfunction and that this in turn may be controlled by changes in cardiac structure and function. This provides an avenue for further investigation.

Additionally, Pillinger et al. provide interesting opportunities for future investigations linking psychiatric disorders to cardiac structure and function. Such studies would improve our understanding of cardiovascular co-morbidities and risk factors associated with psychiatric disorders.

Ultimately, this study, and those which will hopefully soon follow, will help identify new targets for treatment which may improve the life expectancy of individuals with schizophrenia.

Studying the role of genetics in psychiatric disorders and related physical illness may help identify novel targets for treatment, ultimately improving patient care.

Statement of interests

The authors of this blog were involved in the review process of Pillinger et al.’s study and have also published a commentary piece for The Lancet Psychiatry on this article (Parker N and Andreassen OA 2023). Dr. Andreassen reports personal fees from Lundbeck, Sunovion and Janssen (speaker’s honorarium), and Biogen (consultant) outside this written work and is a consultant to cortechs.ai (stock options).

Links

Primary paper

Pillinger T, Osimo EF, Marvao A de, et al. (2023) Impact of polygenic risk for schizophrenia on cardiac structure and function in a UK population-based cohort of over 32,000 people. The Lancet Psychiatry 10(2) 98-107.

Other references

Andreassen OA, Djurovic S, Thompson WK, et al. (2013) Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors. The American Journal of Human Genetics 92(2) 197-209.

Crick D. Does what you eat affect how you feel? The Mental Elf, 8 June 2023.

Hindley G, Frei O, Shadrin AA, et al. (2022) Charting the Landscape of Genetic Overlap Between Mental Disorders and Related Traits Beyond Genetic Correlation. The American Journal of Psychiatry 179(11) 833-843.

Laursen TM, Nordentoft M, Mortensen PB (2014) Excess early mortality in schizophrenia. Annual Review of Clinical Psychology 10 425-448.

Ni G, Zeng J, Revez JA, et al. (2021) A Comparison of Ten Polygenic Score Methods for Psychiatric Disorders Applied Across Multiple Cohorts. Biol Psychiatry 90(9) 611-620.

Parker N, Andreassen OA (2023) Genetic liability to schizophrenia and cardiac structure and function. The Lancet Psychiatry 10(2) 72-73.

Ringen PA, Engh JA, Birkenaes AB, Dieset I, Andreassen OA (2014) Increased Mortality in Schizophrenia Due to Cardiovascular Disease – A Non-Systematic Review of Epidemiology, Possible Causes, and Interventions. Frontiers in Psychiatry 5(137).

Smeland OB, Frei O, Dale AM, Andreassen OA (2020) The polygenic architecture of schizophrenia — rethinking pathogenesis and nosology. Nat Rev Neurol. 16(7) 366-379.

Trubetskoy V, Pardiñas AF, Qi T, et al. (2022) Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 604(7906) 502-508.

Veeneman RR, Vermeulen JM, Abdellaoui A, et al. (2022) Exploring the Relationship Between Schizophrenia and Cardiovascular Disease: A Genetic Correlation and Multivariable Mendelian Randomization Study. Schizophrenia Bulletin 48(2) 463-473.

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