The Genetic Link Between Asthma and Mental Health – Pulmonology Advisor

Asthma has long been associated with lower quality of life as a result of reduced activity and increased psychological stress.1 Indeed, any identified links between asthma and mental health have primarily been unidirectional, with asthma leading to mental illness. However, recent studies have revealed genetic links between asthma and mental health.

Research suggests that people with asthma are more likely to develop mental health problems compared with the general population. In a study conducted with school children, the prevalence of diagnosed mental health conditions among those with asthma was 8.2%, which was nearly double the prevalence among those without asthma (4.8%).2 Another study comprising adults showed that mood disorders were strongly associated with allergic asthma, late-onset asthma, and infection-based asthma.3 In addition, researchers discovered that mental health care services were more likely to be used by people after a diagnosis of asthma.4

More studies are underway to investigate the bidirectional connection between asthma and mental health. One study has linked asthma severity to lifetime and current anxiety, with asthma preceding anxiety in 48% of the patients and anxiety preceding asthma in 52% of the patients.5

There is growing evidence for the involvement of genetics in this asthma-mental health connection. A Swedish study that identified self-report associations between asthma and major depressive disorder (MDD), anxiety, and neuroticism also found genetic correlations between asthma and MDD, but not between asthma and anxiety or neuroticism.6

Another study, a large-scale genome-wide cross trait analysis, has shown a strong association between asthma and 3 mental disorders: attention-deficit/hyperactivity disorder (ADHD), anxiety disorder, and MDD.7 A total of 7 loci were found to be jointly associated with asthma and ADHD; 1 loci with asthma and anxiety disorder; and 10 loci with asthma and MDD.

According to Dr Zhaozhong Zhu, a lead researcher, Mendelian randomization a method of using measured variation in genes of known function was used to infer putative causal relationships between asthma and mental health disorders in both directions, with our results suggesting that ADHD and MDD might increase the risk for asthma. Dr Zhu makes it clear that the mechanism of the association is unknown. The causal relationship found in the study is only based on genetic variables, he explains. The epidemiologic association includes 2 key components: genetics (ie, genes and biological mechanisms) and environment (ie, social factors, exposure to certain conditions [asthma], and medication use).

The study findings indicate genetic causality in the direction of mental illness causing asthma. However, the environmental causality is in the reverse direction and outweighs the genetic causality; thus, the overall epidemiologic causality is in the direction of asthma causing mental health disorders.

Compared with other mental disorders, depression appears to have the strongest link to asthma. In addition to the 10 loci found by Dr Zhu and his team, a single-nucleotide polymorphism (SNP) known as rs4672619, located on the Erb-B2 receptor tyrosine kinase 4 gene, has been implicated in the comorbidity of depression and asthma.8 The researchers who discovered the SNP evaluated the relationship between the depressive status of the individuals and the rs4672619 genotypes on asthma symptom severity. In childhood asthmatics, severe depression was related to less severe asthma symptoms, while in those with heterozygous and homozygous variant alleles, severe depression was related to more severe asthma symptoms.

In elderly patients with asthma, the reverse was true. Those with the homozygous reference allele had a positive correlation between depression and asthma symptom severity, while a negative correlation was seen in those with heterozygous and homozygous variant alleles. Further studies on the relationship between the conditions could lead to the development of personalized therapies for the simultaneous treatment of both conditions.

Few studies have established the genetic link between asthma and anxiety. A Chinese investigation demonstrated the effect of interactions between serotonin transporter (5-HTT), brain-derived neurotrophic factor (BDNF), and the neuropeptide S receptor 1 gene, NPSR1-AS1 polymorphisms on anxiety and depression.9 Interactions between 5-HTT (LL alleles) and BDNF (A+ allele) led to an increased anxiety score, while interactions between BDNF (A+, GG) and NPSR1 (AA, T+) increased the depression score.

While the genetic link between asthma and ADHD was strongly revealed in Dr Zhus study, most other studies have been anecdotal. A large Swedish study found a significant association between asthma and ADHD, even after removing possible confounding variables.10 It has been hypothesized that because asthma and ADHD both have large genetic components, people who are genetically susceptible to one condition may be susceptible to the other.11

Studying genetic variants raises the question of whether any genetic links have cross-cultural implications. While the participants in Dr Zhus research were mainly European, Dr Zhu expects that, Asthma and mental health disorders should be genetically similar, but not the same across major populations, such as African American, Hispanic, or Asian. He points out that one of the shared genetic loci between asthma and MDD, the human leukocyte antigen region on chromosome 6, has a pervasive genetic effect in many diverse populations.

Currently, corticosteroids are considered the most effective long-term treatment for asthma. However, chronic corticosteroid use has been associated with psychosis, depression, anxiety, and mania in people with asthma.12,13 Psychological treatments are being explored as alternative interventions for asthma and while no psychotherapy has been scientifically proven to improve asthma and comorbid mental illness, there has been an increased interest in the use of cognitive behavioral therapy.14,15

Understanding the genetic association between asthma and mental health creates an opportunity for the development of more effective drugs and therapeutic approaches that could treat asthma and associated mental health disorders together. In Dr Zhus study, functional analysis revealed that the identified variants regulated gene expression in tissues of various body systems, including the respiratory and immune system. Thus, further understanding of these variants may lead to treatments that address the respiratory and immune system problems often seen in people asthma.

According to Dr Zhu, In the short term, we aim to inform the general population that mental health disorders can have shared genetic factors with asthma. Therefore, controlling environmental factors, such as eating healthy, enjoying a happy life, and being careful with the potential adverse effects of medication, will help to prevent asthma and mental health disorders. In the long term, with more mechanistic studies, we hope to provide direction in the development of drugs for preventing and treating both conditions at the same time.

References

1. American Academy of Allergy Asthma & Immunology. Increased mental health care use in adults after asthma diagnosis. http://www.aaaai.org/global/latest-research-summaries/New-Research-from-JACI-In-Practice/mental-health. April 7,2017. Accessed November 5, 2019.

2. Lawson J, Rennie D, Dyck R, Cockcroft D, Afanasieva A. The relationship between childhood asthma and mental health conditions.Eur Respir J. 2017;50(suppl 61):PA595.

3. Labor M, Labor S, Juri I, Fijako V, Grle S, Plavec D. Mood disorders in adult asthma phenotypes.J Asthma. 2017;55(1):57-65.

4. To T, Ryckman K, Zhu J, et al. Mental Health Services Claims and Adult Onset Asthma in Ontario, Canada.J Allergy Clin Immunol Pract. 2017;5(5):1388-1393.e3.

5. Del Giacco S, Cappai A, Gambula L, et al. The asthma-anxiety connection.Respir Med. 2016;120:44-53.

6. Lehto K, Pedersen N, Almqvist C, Lu Y, Brew B. Asthma and affective traits in adults: a genetically informative study.Eur Respir J. 2019;53(5):1802142.

7. Zhu Z, Zhu X, Liu C et al. Shared genetics of asthma and mental health disorders: a large-scale genome-wide cross-trait analysis [published online October 17, 2019].Eur Respir J. doi:10.1183.13993003.01507-2019

8. Park H, Song W, Cho S, et al. Assessment of genetic factor and depression interactions for asthma symptom severity in cohorts of childhood and elderly asthmatics. Exp Mol Med. 2018;50(7):77.

9. Yang Y, Zhao M, Zhang Y, Shen X, Yuan Y. Correlation of 5-HTT, BDNF and NPSR1 gene polymorphisms with anxiety and depression in asthmatic patients. Int J Mol Med. 2016;38(1):65-74.

10. Cortese S, Sun S, Zhang J, et al. Association between attention deficit hyperactivity disorder and asthma: a systematic review and meta-analysis and a Swedish population-based study. Lancet Psychiatry. 2018;5(9):717-726.

11. Rapaport L. Links seen between asthma and ADHD. Reuters website. http://www.reuters.com/article/us-health-adhd-asthma/links-seen-between-asthma-and-adhd-idUSKBN1L12FZ. August 15, 2018. Accessed November 14, 2019.

12. Kewalramani A, Bollinger M, Postolache T. Asthma and mood disorders.Int J Child Health Hum Dev. 2008;1(2):115-123.

13. University of Newcastle Australia. Severe Asthma Toolkit. Asthma and Mental Health. https://toolkit.severeasthma.org.au/living-severe-asthma/mental-emotional-health/. Updated February 12, 2019. Accessed November 5, 2019.

14. Kew K, Nashed M, Dulay V, Yorke J. Cognitive behavioural therapy (CBT) for adults and adolescents with asthma.Cochrane Database Syst Rev. 2016;9:CD011818.2

15. Pateraki E, Morris P. Effectiveness of cognitive behavioural therapy in reducing anxiety in adults and children with asthma: a systematic review.J Asthma. 2018;55(5):532-554.

The Genetic Link Between Asthma and Mental Health – Pulmonology Advisor

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