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Genetic Causes of Depression

Having a first-degree relative (parent, sibling or child) with a Depressive Disorder puts an individual at 2-3 times the risk of the general population for developing a Depressive Disorder of their own [ref].   Based on twin-studies (which compare the rates of a condition in identical vs. fraternal twins), it is estimated that about one-third of the risk of developing Major Depressive Disorder can be attributed to inherited factors [ref]. 

There is increasing evidence that variations (also called polymorphisms) of the serotonin transporter gene promoter region (5-HTTLPR) account for some of the risk of developing a Depressive Disorder.   The 5-HTTLPR is a gene that controls the rate at which the serotonin transporter gene is expressed, which in turn determines how much serotonin is available in the central nervous system for signalling to other neurons.  There are two main variations of the 5-HTTLPR gene, the short S type, and the long L type.  The S type causes the body to produce less of the serotonin transporter than the L type, and the S type has been associated with a higher risk of Depression [ref], including Depression following strokes [ref].   Increasingly, it is being recognized that the S type increases the risk of Depression mainly when an individual also experiences significant life-stresses (see here for more information).

(There is a paradox here, for it is thought that the SSRI antidepressants act by blocking the serotonin transporter, so it is hard to understand why a serotonin transporter that naturally functions at a lower level would actually increase the risk of Depression.  One hypothesis is that having a serotonin transporter that is less active throughout one's life may affect the brain differently than when the transporter is blocked only temporarily by an SSRI.  Another hypothesis is that, in this case, the serotonin 2A receptor may be affected more than other serotonin transporters; it seems that increased activity of the serotonin 2A receptor is associated with higher rates of Depression.)  

There are other genes that are also being found to contribute to the risk of Depression.   Certain forms of the dopamine transporter gene DRD2 increase the risk of a person developing Depression following a major life stress [ref].  The tryptophan hydrozylase gene TPH2 also seems to be involved in the occurrence of Depression [ref, ref].

A person's genetic profile may also determine to which antidepressants they are most likely to respond if they become depressed.   One study found that variations in the serotonin transporter gene influence whether or not a person will respond to an antidepressant such as an SSRI, which acts upon serotonin; variations in the norepinephrine transporter gene influence whether or not a person will respond to an antidepressant that acts mainly on the norepinephrine system, such as nortriptyline [ref].

 

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Causes of Depression

Brain Regions