What is depression?
This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
Depression, also known as unipolar depression, is a chronic condition affecting approximately 7% of the US population over 18, with a lifetime risk of 17%. Depressive and anxiety disorders are some of the most common mental disorders in the US, and are highly treatable. This disorder is more commonly diagnosed in women, with a median age of onset of 32.5 [1]. Children and teens are also at risk for depression, with the disorder affecting 12.5% of the US population aged 12-17 [4]. Those suffering from depression will have difficulty conducting daily tasks, such as going to work or school, eating, focusing, taking care of oneself, and interacting with others.
While there are many forms of depression, the focus of this site will be on unipolar depression and its relationship to FKBP5, which will be further discussed below.
While there are many forms of depression, the focus of this site will be on unipolar depression and its relationship to FKBP5, which will be further discussed below.
What are the symptoms and treatments of depression?
Symptoms include, but are not limited to:
Depression can manifest itself in a variety of ways, depending on the sex, age, genotype, and personal experiences of the individual. An individual could experience very few or all of the symptoms above, in varying degrees. For instance, while women may experience feelings of worthlessness and guilt more commonly, men tend to experience more irritability, fatigue, and anger [6]. In order to be diagnosed with depression, one must have at least one depressive episode lasting for two or more weeks. A variety of treatments are currently available to alleviate symptoms, and more treatments are being developed focusing on a more individualized approach using pharmacogenetics [5].
Some of the most common treatments currently available include Cognitive Behavioral Therapy (CBT), which focuses on identifying negative thought patterns and replacing them with positive and beneficial ones, and medications, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) [1]. While many individuals may be helped with only psychotherapy like CBT, it is important to note that all treatments must be individually discussed with a liscenced healthcare provider, as no one treatment works for all individuals.
- Feeling sad, empty, anxious, hopeless, worthless, helpless, and/or guilty
- Loss of interest in hobbies and activities, including sex
- Decrease in energy
- Difficulty concentrating and making decisions
- Weight loss or weight gain
- Irritability and restlessness
- Suicidal thoughts or actions [1]
Depression can manifest itself in a variety of ways, depending on the sex, age, genotype, and personal experiences of the individual. An individual could experience very few or all of the symptoms above, in varying degrees. For instance, while women may experience feelings of worthlessness and guilt more commonly, men tend to experience more irritability, fatigue, and anger [6]. In order to be diagnosed with depression, one must have at least one depressive episode lasting for two or more weeks. A variety of treatments are currently available to alleviate symptoms, and more treatments are being developed focusing on a more individualized approach using pharmacogenetics [5].
Some of the most common treatments currently available include Cognitive Behavioral Therapy (CBT), which focuses on identifying negative thought patterns and replacing them with positive and beneficial ones, and medications, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) [1]. While many individuals may be helped with only psychotherapy like CBT, it is important to note that all treatments must be individually discussed with a liscenced healthcare provider, as no one treatment works for all individuals.
What causes depression?
Depression is caused by a combination of environment, biology, genetics, and psychological factors [6]. While it is often diagnosed with anxiety conditions, there is no evidence one causes the other [5]. Depression can, however, worsen symptoms of other serious illnesses such as cancer and Parkinson's [6].
This site will address the recent studies into the effect of the FKBP5 gene on depression. FKBP5 is responsible for encoding a protein involved in the regulation of the glucocorticoid receptor (GR), as well as many other cellular processes. In the instance of depression, we address the involvement of the GR in various brain tissues, such as the hypothalamus, pituitary, and adrenal (HPA) cortex. Depending on the FKBP5 genotype, a hypersensitivity of the GR in response to cortisol can occur, leading to an increase of cortisol, and therefore stress phenotypes [3].
This site will address the recent studies into the effect of the FKBP5 gene on depression. FKBP5 is responsible for encoding a protein involved in the regulation of the glucocorticoid receptor (GR), as well as many other cellular processes. In the instance of depression, we address the involvement of the GR in various brain tissues, such as the hypothalamus, pituitary, and adrenal (HPA) cortex. Depending on the FKBP5 genotype, a hypersensitivity of the GR in response to cortisol can occur, leading to an increase of cortisol, and therefore stress phenotypes [3].
What is FKBP5 and how does it work?
FKBP5, also known as FK506 binding protein 5 or FKBP51, is a gene located on the sixth chromosome in humans. It encodes four protein variants, depending on alternative splicing. This protein is involved in a variety of conditions due to its effect on the GR.
In depression, it has an inhibitory effect on the GR in brain tissues. This leads to a reduction of hormone binding affinity of glucocorticoid on the GR. When cortisol, the hormone of the glucocorticoid receptor, enters the cell, it complexes with a variety of GR-stimulatory factors. This complex can then enter the nucleus and bind to DNA, where it can alter transcription of specific genes, and therefore alter gene expression. In depression, the FKBP5 protein competes for access to the Hsp90-GR heterocomplex. This prevents the binding of stimulatory factors [3].
This gene also has multiple alleles, some of which are more highly associated with a depression disease phenotype, dependent on population. These alleles vary by a single nucleotide base in an intronic region of the gene. Individuals can either be C/C, C/T, or T/T.
The FKBP5 gene can be epigenetically altered. Following the addition of a post-translational modification, the gene can be more or less susceptible to transcription than the non-modified version, depending on the type of modifications. In the instance of depression, a decrease of DNA methylation in an intronic regulatory element is observed, leading to an increase of FKBP5 mRNA production [2]. As a result of FKBP5 mRNA production, more FKBP5 protein is produced, and more GRs are prevented from properly binding to their stimulatory factors and circulating cortisol levels are increased. The chronic exposure to cortisol, or corticosterone, has been linked to an increase of fkbp5 mRNA in the hippocampus, hypothalamus, and blood [2]. In normal function, cortisol is released as a response to a stressor, such as a nearby danger, or a period of fasting, when your body needs to break down proteins into glucose for energy. If too much cortisol is present in the body, it can lead to unnecessary feelings of anxiety, as if there was a threat that needed to be avoided, despite there being no nearby threat.
In depression, it has an inhibitory effect on the GR in brain tissues. This leads to a reduction of hormone binding affinity of glucocorticoid on the GR. When cortisol, the hormone of the glucocorticoid receptor, enters the cell, it complexes with a variety of GR-stimulatory factors. This complex can then enter the nucleus and bind to DNA, where it can alter transcription of specific genes, and therefore alter gene expression. In depression, the FKBP5 protein competes for access to the Hsp90-GR heterocomplex. This prevents the binding of stimulatory factors [3].
This gene also has multiple alleles, some of which are more highly associated with a depression disease phenotype, dependent on population. These alleles vary by a single nucleotide base in an intronic region of the gene. Individuals can either be C/C, C/T, or T/T.
The FKBP5 gene can be epigenetically altered. Following the addition of a post-translational modification, the gene can be more or less susceptible to transcription than the non-modified version, depending on the type of modifications. In the instance of depression, a decrease of DNA methylation in an intronic regulatory element is observed, leading to an increase of FKBP5 mRNA production [2]. As a result of FKBP5 mRNA production, more FKBP5 protein is produced, and more GRs are prevented from properly binding to their stimulatory factors and circulating cortisol levels are increased. The chronic exposure to cortisol, or corticosterone, has been linked to an increase of fkbp5 mRNA in the hippocampus, hypothalamus, and blood [2]. In normal function, cortisol is released as a response to a stressor, such as a nearby danger, or a period of fasting, when your body needs to break down proteins into glucose for energy. If too much cortisol is present in the body, it can lead to unnecessary feelings of anxiety, as if there was a threat that needed to be avoided, despite there being no nearby threat.
What are Epigenetics?
In a given cell, gene expression is regulated through a variety of factors. One of these factors is epigenetics, which is the alteration of genomic structure to react to changing cellular conditions rather than changing the genomic sequence. These kinds of modifications are essential for cell survival. While there are many types of epigenetic mechanisms, some of the most common are DNA methylation and histone methylation or acetylation [2]. These post-translational modifications affect gene expression by altering the availability of the DNA. If transcriptional machinery cannot access the DNA, the gene cannot be expressed, and its corresponding proteins will not be produced by the cell.
When it comes to FKBP5, the main epigenetic mechanism involved is DNA methylation. When DNA is methylated, it is more tightly compacted, preventing it from being transcribed. When methylation decreases, the DNA is more available for transcription, leading to an increase of that gene's mRNA transcripts. In depressed patients, FKBP5 is less methylated in an essential intronic segment, allowing the gene to be highly transcribed[8]. It is important to note, however, that only the cytidine (C) nucleotide can be methylated. This links to the genotype of FKBP5 through the existence of a risk allele and a protective allele. The protective C allele can be methylated, preventing enhanced transcription through DNA compaction. However, the T risk allele does not share this ability to be methylated and is hypothesized to form a TATA-box like sequence, which would enhance the transcriptional ability[9].
When it comes to FKBP5, the main epigenetic mechanism involved is DNA methylation. When DNA is methylated, it is more tightly compacted, preventing it from being transcribed. When methylation decreases, the DNA is more available for transcription, leading to an increase of that gene's mRNA transcripts. In depressed patients, FKBP5 is less methylated in an essential intronic segment, allowing the gene to be highly transcribed[8]. It is important to note, however, that only the cytidine (C) nucleotide can be methylated. This links to the genotype of FKBP5 through the existence of a risk allele and a protective allele. The protective C allele can be methylated, preventing enhanced transcription through DNA compaction. However, the T risk allele does not share this ability to be methylated and is hypothesized to form a TATA-box like sequence, which would enhance the transcriptional ability[9].
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Citations:
[1]Anxiety and Depression Association of America. (August 2016). Retrieved from https://www.adaa.org
[2]Dias, Brian G. (2015) Epigenetic mechanisms underlying learning and the inheritance of learned behaviors. Trends in Neurosciences.
[3]Touma, C. et al. (2011) FK506 binding protein 5 shapes stress responsiveness: modulation of neuroendocrine reactivity and coping behavior. Biol. Psychiatry 70, 928–936
[4] National Institutes of Health. Major Depression among Adolescents. (2015). Retrieved from https://www.nimh.nih.gov/health/statistics/prevalence/major-depression-among-adolescents.shtml
[5]Fabbri, C. & Serretti, A. Curr Psychiatry Rep (2015) Pharmacogenetics of Major Depressive Disorder: Top Genes and Pathways Toward Clinical Applications. 17: 50. doi:10.1007/s11920-015-0594-9
[6] National Institutes of Mental Health. Depression Basics. Retrieved from https://www.nimh.nih.gov/health/publications/depression/index.shtml#pub4
[7] Ellsworth, Katarzyna Anna and Wang, Liewei. FKBP5 (FK506 binding Protein 5). (2010). Retrieved from http://atlasgeneticsoncology.org/Genes/FKBP5ID40578ch6p21.html
[8]Ferrell, C. et. al. (2016) Epigenetics and the glucocorticoid receptor: a review of the implications of depression. Psychiatry Research. doi: 10.1016/j.psychres.2016.06.022
[9]Klengel, T. et al. (2013). Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature Neuroscience. doi:10.1038/nn.3275.
To access photo source, click on image.
Header photo from https://www.novusbio.com/products/fkbp51-fkbp5-antibody-3e9_nbp1-47755.
[1]Anxiety and Depression Association of America. (August 2016). Retrieved from https://www.adaa.org
[2]Dias, Brian G. (2015) Epigenetic mechanisms underlying learning and the inheritance of learned behaviors. Trends in Neurosciences.
[3]Touma, C. et al. (2011) FK506 binding protein 5 shapes stress responsiveness: modulation of neuroendocrine reactivity and coping behavior. Biol. Psychiatry 70, 928–936
[4] National Institutes of Health. Major Depression among Adolescents. (2015). Retrieved from https://www.nimh.nih.gov/health/statistics/prevalence/major-depression-among-adolescents.shtml
[5]Fabbri, C. & Serretti, A. Curr Psychiatry Rep (2015) Pharmacogenetics of Major Depressive Disorder: Top Genes and Pathways Toward Clinical Applications. 17: 50. doi:10.1007/s11920-015-0594-9
[6] National Institutes of Mental Health. Depression Basics. Retrieved from https://www.nimh.nih.gov/health/publications/depression/index.shtml#pub4
[7] Ellsworth, Katarzyna Anna and Wang, Liewei. FKBP5 (FK506 binding Protein 5). (2010). Retrieved from http://atlasgeneticsoncology.org/Genes/FKBP5ID40578ch6p21.html
[8]Ferrell, C. et. al. (2016) Epigenetics and the glucocorticoid receptor: a review of the implications of depression. Psychiatry Research. doi: 10.1016/j.psychres.2016.06.022
[9]Klengel, T. et al. (2013). Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature Neuroscience. doi:10.1038/nn.3275.
To access photo source, click on image.
Header photo from https://www.novusbio.com/products/fkbp51-fkbp5-antibody-3e9_nbp1-47755.