Changes In Chromosome 15 In Adolescents With Major Depressive And Anxiety Disorders

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:

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