Changes In Chromosome 15 In Adolescents With Major Depressive And Anxiety Disorders - Science Trends

Published by Madelyn Gillentine and Christian Schaaf

Baylor College of Medicine, Texas Children’s Hospital, University of Washington, and the University of Cologne

These findings are described in the article entitled CHRNA7 copy number gains are enriched in adolescents with major depressive and anxiety disorders, recently published in the Journal of Affective Disorders (Journal of Affective Disorders 239 (2018) 247-252). This work was conducted by Madelyn A. Gillentine from Baylor College of Medicine, Texas Children’s Hospital, and the University of Washington, Ricardo Lozoya from Texas Children’s Hospital, Jiani Yin from Baylor College of Medicine and Texas Children’s Hospital, Christopher M. Grochowski, Janson J. White, and Chadi A. Calarge from Baylor College of Medicine, and Christian P. Schaaf from Baylor College of Medicine, Texas Children’s Hospital, University Hospital Cologne, and the University of Cologne.

Major depressive disorder (MDD) and anxiety disorders are among the most prevalent neuropsychiatric diagnoses, estimated to affect about one-third of adults and adolescents in the United States (1,2). Treatment of such disorders has improved, but many patients are still treated with drugs whose mechanisms in the brain are not understood, resulting in a trial and error process of drugs to find the best fit. With the increased utilization of pharmacogenomics in the clinic (the use of a patient’s DNA to inform what therapeutic drugs may appropriate), it is important to understand if there are genetic changes among those diagnosed with MDD and/or anxiety disorders that may be targets for therapeutics.

Chromosome 15, specifically region 15q13.3, is among the least stable regions in the genome. Due to highly similar DNA sequences, genes are often deleted or duplicated in this region, both with negative consequences (3). Deletions are clinically well characterized, resulting in 15q13.3 microdeletion syndrome, in which individuals tend to have an intellectual disability/developmental delay (ID/DD), epilepsy, and autism spectrum disorder (ASD) (4). These deletions are rare, occurring in about 1 in 5000 individuals (5).

Duplications at 15q13.3 are less understood, despite their much higher occurrence in both clinical and control samples (1 in 123 and 1 in 164, respectively) (6). While it has been suggested that these duplications are not deleterious due to their high prevalence in all populations, we believe that these duplications are likely responsible for individuals who have milder neuropsychiatric traits that are undiagnosed, including anxiety disorders and major depressive disorder (MDD). Based on the literature, individuals with 15q13.3 duplications mostly exhibit ID/DD, schizophrenia, and mood disorders such as anxiety, depression, and bipolar disorder (3,6).

For both deletions and duplications of this region, there is a strong candidate gene, CHRNA7 (3). CHRNA7 encodes for the α7 nicotinic acetylcholine receptor (nAChR), a member of a family of genes known to be critical in the brain for learning and memory and implicated in multiple neuropsychiatric disorders (7). While its function makes it a good candidate gene for the diagnoses we observe, it is also an exciting gene as it produces a protein that is targetable by pharmacological compounds. Several drugs targeting the α7 nAChR have been used in small studies for individuals with schizophrenia and autism spectrum disorder, with promising results (8-12).

Since individuals with 15q13.3 duplications, or CHRNA7 duplications, exhibit a high rate of mood disorders, the authors wanted to assess if these genetic changes are a risk factor for mood disorders broadly (13). To this end, they designed an assay using droplet digital PCR, which allows for rapid screening of DNA samples for a genetic change of choice. As CHRNA7 is a likely causative gene in the 15q13.3 region, they chose to focus on this gene for the assay. Using this, 205 DNA samples from adolescents with anxiety and/or depression were screened. Five (2.4%) of these carried CHRNA7 duplications, which is four-fold what has been reported in the general population, suggesting that these duplications increase the risk of anxiety and depression by four times. No deletions were identified, which is in line with their differing clinical traits. For this subset of individuals, treatment with drugs targeting the α7 nAChR may prove beneficial. However, there were no significant differences behaviorally between the individuals with duplications versus those without. Therefore, to identify such individuals, genomic assays would be necessary, which are not typically performed in psychiatry clinics. Overall, this study works towards more targeted and effective treatment of anxiety and depression.

References:

1. Bandelow, B., and Michaelis, S. (2015). Epidemiology of anxiety disorders in the 21st century. Dialogues Clin Neurosci 17, 327–335.
2. Merikangas, K., He, J., Burstein, M., Swanson, S., Avenevoli, S., Cui, L., Benjet, C., Georgiades, K., and Swendsen, J. (2010). Lifetime Prevalence of Mental Disorders in U.S. Adolescents: Results from the National Comorbidity Survey Replication–Adolescent Supplement (NCS-A). Journal of the American Academy of Child & Adolescent Psychiatry 49, 980–989.
3. Gillentine, M.A., and Schaaf, C.P. (2015). The human clinical phenotypes of altered CHRNA7 copy number. Biochem. Pharmacol. 97, 352–362.
4. Ziats, M.N., Goin-Kochel, R.P., Berry, L.N., Ali, M., Ge, J., Guffey, D., Rosenfeld, J.A., Bader, P., Gambello, M.J., Wolf, V., et al. (2016). The complex behavioral phenotype of 15q13.3 microdeletion syndrome. Genet. Med. 18, 1111–1118.
5. Gillentine, M.A., Lupo P.J., Stankiewicz, P., Schaaf, C.P. (2018) An estimation of the prevalence of genomic disorders using chromosomal microarray data. J. Hum Genet. 63(7):795-801
6. Gillentine, M.A., Berry, L.N., Goin-Kochel, R.P., Ali, M.A., Ge, J., Guffey, D., Rosenfeld, J.A., Hannig, V., Bader, P., Proud, M., et al. (2017). The Cognitive and Behavioral Phenotypes of Individuals with CHRNA7 Duplications. J Autism Dev Disord 47, 549–562.
7. Schaaf, C. (2014). Nicotinic acetylcholine receptors in human genetic disease. Genetics in Medicine : Official Journal of the American College of Medical Genetics 16, 649–656.
8. Freedman, R., Olincy, A., Buchanan, R.W., Harris, J.G., Gold, J.M., Johnson, L., Allensworth, D., Guzman-Bonilla, A., Clement, B., Ball, M.P., et al. (2008). Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry 165, 1040–1047.
9. Walling, D., Marder, S.R., Kane, J., Fleischhacker, W.W., Keefe, R.S., Hosford, D.A., Dvergsten, C., Segreti, A.C., Beaver, J.S., Toler, S.M., et al. (2016). Phase 2 Trial of an Alpha-7 Nicotinic Receptor Agonist (TC-5619) in Negative and Cognitive Symptoms of Schizophrenia. Schizophr Bull 42, 335– 343.
10. Freedman, R. (2014). α7-nicotinic acetylcholine receptor agonists for cognitive enhancement in schizophrenia. Annu. Rev. Med. 65, 245–261.
11. Olincy, A., and Freedman, R. (2012). Nicotinic mechanisms in the treatment of psychotic disorders: a focus on the α7 nicotinic receptor. Handb Exp Pharmacol 211–232.
12. Olincy, A., Blakeley-Smith, A., Johnson, L., Kem, W.R., and Freedman, R. (2016). Brief Report: Initial Trial of Alpha7-Nicotinic Receptor Stimulation in Two Adult Patients with Autism Spectrum Disorder. J Autism Dev Disord 46, 3812– 3817.
13. Gillentine, M.A., Lozoya, R., Yin., J., Grochowski, C.M., White, J.J., Schaaf, C.P., Calarge, C.A. 2018. CHRNA7 copy number gains are enriched in adolescents with major depressive and anxiety disorders. J. Affect Disord. 239: 247-252

About The Author(s)

Madelyn Gillentine is a Senior Postdoctoral Fellow at University of Washington

Christian Schaaf, MD, PhD is the Joan and Stanford Alexander Endowed Chair for Neuropsychiatric Genetics at Baylor College of Medicine, Department of Molecular and Human Genetics.

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