This web page was produced as an assignment for Genetics 564, an undergraduate course at UW-Madison
About Obsessive Compulsive Disorder
Obsessive Compulsive Disorder (OCD) is a condition profiled in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as a thought disorder in which there are urges to repeat some behavior. These urges are defined as obsessions and compulsions [1]. Obsessions are classified as unwanted thoughts, urges, or images that are unable to be ignored. Compulsions are the repetitive behaviors or thoughts performed in order to alleviate anxiety that stems from obsessions [1].
DSM-5 Criteria for Obsessive Compulsive Disorder [6]
There must be obsessions, compulsions, or both.
Obsessions are considered:
Obsessions are considered:
- Thoughts or drives that are invasive, unshakeable, and most importantly, unwanted or distressing to the individual experiencing them
- Because of this distress, the individual attempts to ignore them but is often physically unable to do so
- Repetitive behaviors or rituals with strict rules that the individual performs to prevent the anxiety or discomfort that accompanies their obsessions
Based on previous twin studies performed around the world, the heritability of OCD is approximately 50% [2,3,4, among others]. One major factor that is thought to be connected to characteristics of this disorder is the SLC6A4 gene in humans (also referred to as 5-HTTLPR, 5-HTT, and SERT1 [5]).
SLC6A4: The Gene
The SLC6A4 gene, which stands for "solute carrier family 6 (neurotransmitter transporter), member 4," is located on chromosome 17, at location 17q11.2 as indicated by the yellow arrow on the image to the left [5]. It has 14 exons that span approximately 31,000 bp and twelve introns scattered throughout those coding segments. SLC6A4 and its 5'-flanking promoter region have been studied extensively in the last few decades and have been linked to development of OCD [9].
There are a number of known alleles and polymorphisms in SLC6A4, some of which are thought to play a role in OCD onset. Three of these alleles can be distinguished by the number of 17-bp tandem repeats in part of intron 2. They have been named STin2.9, STin2.10, and STin2.12, because they have 9, 10, and 12 copies of the repeats (see Figure 1 below). All have been correlated to affective disorders such as anxiety and depression, and the co-occurrence of these types of disorders with OCD makes the alleles indirectly associated to OCD as well [7].
In addition, the polymorphism 5-HTTLPR has a 44-bp insertion or deletion which affects expression of the promoter sequence for SLC6A4 [14]. This results in a long (L) and short (S) version of the gene. Within the insertion sequence of the L allele, there can also be a point mutation in which an adenine is substituted with guanine. This gives alternative LA and LG alleles (see Figure 2 below). Studies by Hu et al. have shown the gain-of-function allele LA, especially in the LA/LA combination, was more common in patients with OCD, increasing their risk of OCD development by 1.8-fold. Though this is not a significant increase when compared to the risk from having a first-degree family member with OCD, it is likely a factor in the overall polygenic expression of the OCD phenotype [8].
There are a number of known alleles and polymorphisms in SLC6A4, some of which are thought to play a role in OCD onset. Three of these alleles can be distinguished by the number of 17-bp tandem repeats in part of intron 2. They have been named STin2.9, STin2.10, and STin2.12, because they have 9, 10, and 12 copies of the repeats (see Figure 1 below). All have been correlated to affective disorders such as anxiety and depression, and the co-occurrence of these types of disorders with OCD makes the alleles indirectly associated to OCD as well [7].
In addition, the polymorphism 5-HTTLPR has a 44-bp insertion or deletion which affects expression of the promoter sequence for SLC6A4 [14]. This results in a long (L) and short (S) version of the gene. Within the insertion sequence of the L allele, there can also be a point mutation in which an adenine is substituted with guanine. This gives alternative LA and LG alleles (see Figure 2 below). Studies by Hu et al. have shown the gain-of-function allele LA, especially in the LA/LA combination, was more common in patients with OCD, increasing their risk of OCD development by 1.8-fold. Though this is not a significant increase when compared to the risk from having a first-degree family member with OCD, it is likely a factor in the overall polygenic expression of the OCD phenotype [8].
Figure 1: The tandem repeat-region of intron 2, in which the 17-bp segment listed is repeated 9, 10, and 12 times respectively in the STin2.9, STin2.10, and STin2.12 alleles.
|
Figure 2: A polymorphism found in the 5'-flanking promoter region of the SLC6A4 gene causes formation of a long (L) and short (S) allele. The L allele can also exhibit a point mutation in part of the insertion. The LA allele has been found to be associated most often with OCD.
|
The SLC6A4 gene is expressed primarily in the central nervous system, in neurons that are involved in serotonin release and reuptake. However, it can also be found in platelet, pulmonary, and placental membranes to a lesser degree. Because OCD is considered a psychological disorder, neuronal transmitters will be the focus of discussion [10].
SLC6A4: The Protein
As the name implies, SLC6A4 codes for a protein that deals with transport of a neurotransmitter. More specifically, this protein is found in the membrane of presynaptic neurons and brings about the reuptake of serotonin from the synaptic gap. Here, serotonin remains stored until its release is signaled again. Ultimately, this prevents serotonin from acting upon post-synaptic receptors and constitutively sending its message because it is physically cleared from the synaptic gap altogether [9].
Figure 3: On the right, an example of a synaptic gap. The presynaptic neuron is the storage place for neurotransmitters that that get sent out into the synaptic gap. Once released they can traverse this gap to interact with receptors on the post-synaptic neuron. The SLC6A4 protein is located in the membrane of the presynaptic neuron and induces the reuptake of serotonin for storage. This is just one of many neurotransmitters that can be released in the brain, functioning mainly in regulation of sleep, appetite, and emotion [11].
|
The SLC6A4 protein is 630 amino acids long and traverses the neuronal membrane twelve times. All twelve transmembrane segments are alpha-helices, as seen in the computerized structure to the left. They are mostly composed of hydrophobic amino acids, whereas the cytoplasmic and extracellular portions of the protein have an even mixture of hydrophobic and hydrophilic residues [12]. This is fitting with a transmembrane protein because cell membranes are composed of highly nonpolar lipids. Transmembrane segments are therefore going to contain a large majority of hydrophobic amino acids, allowing them to interact favorably with the membrane. The segments that project out of the membrane are composed of amino acids that help SLC6A4 interact with various proteins or serotonin molecules that it comes into contact with.
SLC6A4, along with the other proteins within the SLC6 family, are reliant upon solutes to function properly. When serotonin needs to be transported by SLC6A4, there first has to be a change in the electrochemical gradients of sodium, chloride, and potassium ions. The inside of the cell remains more negative than the outside by pumping more positive sodium ions out of the cell than positive potassium ions in. When serotonin is to be brought back into the presynaptic neuron, a signal from the brain tells sodium ions to fall down their electrochemical gradient into the cell to release enough energy for serotonin reuptake to occur. Since sodium ions are positively charged, they also attract negative chloride ions to move into the cell. Therefore, SLC6A4 is solute-dependent on sodium, potassium, and chloride [13].
SLC6A4, along with the other proteins within the SLC6 family, are reliant upon solutes to function properly. When serotonin needs to be transported by SLC6A4, there first has to be a change in the electrochemical gradients of sodium, chloride, and potassium ions. The inside of the cell remains more negative than the outside by pumping more positive sodium ions out of the cell than positive potassium ions in. When serotonin is to be brought back into the presynaptic neuron, a signal from the brain tells sodium ions to fall down their electrochemical gradient into the cell to release enough energy for serotonin reuptake to occur. Since sodium ions are positively charged, they also attract negative chloride ions to move into the cell. Therefore, SLC6A4 is solute-dependent on sodium, potassium, and chloride [13].
Treatment for OCD [15]
Because OCD is a disorder that strongly affects behavior, many of the common treatments today work toward behavioral modification through Exposure and Response Prevention Therapy. An individual with undesirable compulsions will be exposed to a trigger that sets off those behaviors. However, any compulsive behavioral responses are prevented and the person is forced to wait out their anxiety until they feel like they can move on to a different activity. Eventually, if exposure occurs often enough, anxiety levels will drop and the individual will no longer feel like the compulsions are necessary. This is always initiated with trained behavioral specialists, though individuals can learn to do it themselves to manage their symptoms.
As discussed above, OCD is also a neurological disorder in which serotonin is largely affected. For this reason, antidepressant medications called Serotonin Reuptake Inhibitors (SRIs) are commonly prescribed to people with OCD. If taken as prescribed and coupled with Exposure and Response Prevention, about 70% of people will see a significant reduction in their symptoms [15]. However, undesirable side effects of these medications often cause patients to stop using them and cause the return of their original symptoms. For continued effectiveness, these drugs generally need to be taken for life.
As discussed above, OCD is also a neurological disorder in which serotonin is largely affected. For this reason, antidepressant medications called Serotonin Reuptake Inhibitors (SRIs) are commonly prescribed to people with OCD. If taken as prescribed and coupled with Exposure and Response Prevention, about 70% of people will see a significant reduction in their symptoms [15]. However, undesirable side effects of these medications often cause patients to stop using them and cause the return of their original symptoms. For continued effectiveness, these drugs generally need to be taken for life.
It is important to remember that OCD is a disease, just like diabetes. It can be treated, but oftentimes the symptoms continue to be a burden. This can cause individuals to be isolated from family or friends and ultimately have severe physical and mental effects, including depression. Watch the video above for a personal look at the effects of OCD on one Madison man.
References
[1] What is OCD? (2014, April 28). Retrieved February 5, 2015, from http://iocdf.org/about-OCD/
[2] Iervolino, A., Rijsdijk, F., Cherkas, L., Fullana, M., & Mataix-Cols, D. (2011). A Multivariate Twin Study of Obsessive-Compulsive Symptom Dimensions. Archives of General Psychiatry, 68(6), 637-644. Retrieved February 5, 2015, from http://archpsyc.jamanetwork.com.ezproxy.library.wisc.edu/article.aspx?articleid=912992
[3]Hudziak, J., Van Beijsterveldt, C., Althoff, R., Stanger, C., Rettew, D., Nelson, E., ... Boomsma, D. (2004). Genetic and Environmental Contributions to the Child Behavior ChecklistObsessive-Compulsive Scale. Archives of General Psychiatry, 61(6), 608-616. Retrieved February 5, 2015, from http://archpsyc.jamanetwork.com.ezproxy.library.wisc.edu/article.aspx?articleid=482012
[4] López-Solà, C., Fontenelle, L., Alonso, P., Cuadras, D., Foley, D., Pantelis, C., ... Harrison, B. (2014). Prevalence and heritability of obsessive-compulsive spectrum and anxiety disorder symptoms: A survey of the Australian Twin Registry. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 165(4), 314-325. Retrieved February 5, 2015, from http://onlinelibrary.wiley.com.ezproxy.library.wisc.edu/doi/10.1002/ajmg.b.32233/full
[5] SLC6A4 gene. (2015, February 9). Retrieved February 15, 2015, from http://ghr.nlm.nih.gov/gene/SLC6A4
[6] Kring, A., & Johnson, S. (2013). Obsessive-Compulsive and Related Disorders. In Abnormal Psychology (12th ed. ed., DSM-5 Update, pp. 202-213). Hoboken, N.J.: John Wiley & Sons.
[7] Ogilvie, A., Battersby, S., Fink, G., Harmar, A., Goodwin, G., Bubb, V., & Smith, C. (1996). Polymorphism in serotonin transporter gene associated with susceptibility to major depression. The Lancet, 347(9003), 731-733. Retrieved February 18, 2015, from http://www.sciencedirect.com.ezproxy.library.wisc.edu/science/article/pii/S0140673696900793
[8] Hu, X., Lipsky, R., Zhu, G., Akhtar, L., Taubman, J., Greenberg, B., ... Kennedy, J. (2006). Serotonin Transporter Promoter Gain-of-Function Genotypes Are Linked To Obsessive-Compulsive Disorder. The American Journal of Human Genetics, 78(5), 815-826. Retrieved February 18, 2015, from http://www.sciencedirect.com/science/article/pii/S0002929707638166
[9] Lesch, K., Balling, U., Gross, J., Strauss, K., Wolozin, B., Murphy, D., & Riederer, P. (1994). Organization of the human serotonin transporter gene. Journal of Neural Transmission, 95(2), 157-162. Retrieved February 18, 2015, from http://link.springer.com.ezproxy.library.wisc.edu/article/10.1007/BF01276434
[10] Ramamoorthy, S., Bauman, A., Moore, K., Han, H., Yang-Feng, T., Chang, A., ... Blakely, R. (1993). Antidepressant- And Cocaine-Sensitive Human Serotonin Transporter: Molecular Cloning, Expression, And Chromosomal Localization. Proceedings of the National Academy of Sciences, 90(6), 2542-2546. Retrieved February 18, 2015, from http://www.pnas.org/content/90/6/2542.long
[11] Mandal, A. (2014, February 13). Serotonin Function. Retrieved May 6, 2015, from http://www.news-medical.net/health/Serotonin-Function.aspx
[12] SLC6A4 - Sodium-dependent serotonin transporter - Homo sapiens (Human). (n.d.). Retrieved February 19, 2015, from http://www.uniprot.org/uniprot/P31645
[13] Mechanism of action of the serotonin transporter. (n.d.). Retrieved February 19, 2015, from http://web.williams.edu/imput/IVB3.html
[14] Nakamura, M., Ueno, S., Sano, A., & Tanabe, H. (2000). The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Molecular Psychiatry, 5(1), 32-38. Retrieved February 19, 2015, from http://www.nature.com/mp/journal/v5/n1/full/4000698a.html
[15] How is OCD Treated? (2014, April 28). Retrieved February 19, 2015, from https://iocdf.org/about-ocd/treatment/
[2] Iervolino, A., Rijsdijk, F., Cherkas, L., Fullana, M., & Mataix-Cols, D. (2011). A Multivariate Twin Study of Obsessive-Compulsive Symptom Dimensions. Archives of General Psychiatry, 68(6), 637-644. Retrieved February 5, 2015, from http://archpsyc.jamanetwork.com.ezproxy.library.wisc.edu/article.aspx?articleid=912992
[3]Hudziak, J., Van Beijsterveldt, C., Althoff, R., Stanger, C., Rettew, D., Nelson, E., ... Boomsma, D. (2004). Genetic and Environmental Contributions to the Child Behavior ChecklistObsessive-Compulsive Scale. Archives of General Psychiatry, 61(6), 608-616. Retrieved February 5, 2015, from http://archpsyc.jamanetwork.com.ezproxy.library.wisc.edu/article.aspx?articleid=482012
[4] López-Solà, C., Fontenelle, L., Alonso, P., Cuadras, D., Foley, D., Pantelis, C., ... Harrison, B. (2014). Prevalence and heritability of obsessive-compulsive spectrum and anxiety disorder symptoms: A survey of the Australian Twin Registry. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 165(4), 314-325. Retrieved February 5, 2015, from http://onlinelibrary.wiley.com.ezproxy.library.wisc.edu/doi/10.1002/ajmg.b.32233/full
[5] SLC6A4 gene. (2015, February 9). Retrieved February 15, 2015, from http://ghr.nlm.nih.gov/gene/SLC6A4
[6] Kring, A., & Johnson, S. (2013). Obsessive-Compulsive and Related Disorders. In Abnormal Psychology (12th ed. ed., DSM-5 Update, pp. 202-213). Hoboken, N.J.: John Wiley & Sons.
[7] Ogilvie, A., Battersby, S., Fink, G., Harmar, A., Goodwin, G., Bubb, V., & Smith, C. (1996). Polymorphism in serotonin transporter gene associated with susceptibility to major depression. The Lancet, 347(9003), 731-733. Retrieved February 18, 2015, from http://www.sciencedirect.com.ezproxy.library.wisc.edu/science/article/pii/S0140673696900793
[8] Hu, X., Lipsky, R., Zhu, G., Akhtar, L., Taubman, J., Greenberg, B., ... Kennedy, J. (2006). Serotonin Transporter Promoter Gain-of-Function Genotypes Are Linked To Obsessive-Compulsive Disorder. The American Journal of Human Genetics, 78(5), 815-826. Retrieved February 18, 2015, from http://www.sciencedirect.com/science/article/pii/S0002929707638166
[9] Lesch, K., Balling, U., Gross, J., Strauss, K., Wolozin, B., Murphy, D., & Riederer, P. (1994). Organization of the human serotonin transporter gene. Journal of Neural Transmission, 95(2), 157-162. Retrieved February 18, 2015, from http://link.springer.com.ezproxy.library.wisc.edu/article/10.1007/BF01276434
[10] Ramamoorthy, S., Bauman, A., Moore, K., Han, H., Yang-Feng, T., Chang, A., ... Blakely, R. (1993). Antidepressant- And Cocaine-Sensitive Human Serotonin Transporter: Molecular Cloning, Expression, And Chromosomal Localization. Proceedings of the National Academy of Sciences, 90(6), 2542-2546. Retrieved February 18, 2015, from http://www.pnas.org/content/90/6/2542.long
[11] Mandal, A. (2014, February 13). Serotonin Function. Retrieved May 6, 2015, from http://www.news-medical.net/health/Serotonin-Function.aspx
[12] SLC6A4 - Sodium-dependent serotonin transporter - Homo sapiens (Human). (n.d.). Retrieved February 19, 2015, from http://www.uniprot.org/uniprot/P31645
[13] Mechanism of action of the serotonin transporter. (n.d.). Retrieved February 19, 2015, from http://web.williams.edu/imput/IVB3.html
[14] Nakamura, M., Ueno, S., Sano, A., & Tanabe, H. (2000). The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Molecular Psychiatry, 5(1), 32-38. Retrieved February 19, 2015, from http://www.nature.com/mp/journal/v5/n1/full/4000698a.html
[15] How is OCD Treated? (2014, April 28). Retrieved February 19, 2015, from https://iocdf.org/about-ocd/treatment/
Header, Videos, and Interactive Map:
Header http://www.foundationscounselingllc.com/obsessive-compulsive-disorder-therapy.php OCD - What Is Obsessive Compulsive Disorder? https://www.youtube.com/watch?v=IGKW-iWOar8 Neil Hilborn - "OCD" (Rustbelt 2013) https://www.youtube.com/watch?v=vnKZ4pdSU- World Map http://whos.amung.us/ |
Pictures from top to bottom of page:
http://www.grcounselling.com.au/ocd-symptoms-treatment-melbourne.html http://ghr.nlm.nih.gov/gene/SLC6A4 http://www.sciencedirect.com.ezproxy.library.wisc.edu/science/article/pii/S0140673696900793 http://www.sciencedirect.com/science/article/pii/S0002929707638166 http://healthadviser24.blogspot.com/2012/08/neurotransmitters-chemical-messenger-of.html http://commons.wikimedia.org/wiki/File:Serotonin-skeletal.png http://www.proteopedia.org/wiki/index.php/Image:SERT_image.png |
Site Created By: Maisie Steinbrink
Last Updated 5/17/15
University of Wisconsin - Madison
Genetics 564
Last Updated 5/17/15
University of Wisconsin - Madison
Genetics 564