Anxiety & Depression 5-HTTLPR Test

The S-allele is one of two common variations in a polymorphic region (5-HTTLPR) of the SLC6A4 gene, which encodes the 5-HTT serotonin transporter. This S-allele is the short variant of 5-HTTLPR, as it contains only 14 copies of a repetitive sequence element, compared to the 16 copies in the long variant (L-allele). This deletion results in lower production of the serotonin transporter, and smaller amygdala and cingulate regions – two brain regions involved in emotional responses. The S-allele is linked to an increased risk of grumpy or sad feelings, and an increased risk of a variety of psychological conditions like depression, bipolar disorder, attention deficit disorder and Alzheimer’s disease, as well as addictive behaviors and sudden infant death syndrome. The S-allele is often referred to as the “grouchy” gene.

The SLC6A4 gene is located on an autosome (chromosome 17). Autosomes are inherited in pairs – one from each parent; hence people carry two copies of the SLC6A4 gene. Inheriting one or two copies of the S-allele is linked to an increased risk of anxiety and depression.

The S-allele is commonly called the “grouchy” gene due to its association with unhappiness. Other studies have also linked the 5-HTTLPR short form to other conditions including:

• Anxiety related behaviour and stress response
• Antisocial behaviour
• Impulsiveness
• Attention deficit disorder
• Psychological disorders such as autism, depression, bipolar disorder
• Addictive behaviour
• Sudden infant death syndrome
• Response to antidepressants

The S-allele of the SLC6A4 gene is associated with a decreased response to selective serotonin reuptake inhibitor (SSRI) antidepressants. Examples of commonly prescribed SSRIs include fluoxetine (Prozac), paroxetine (Paxil, Paxil CR), citalopram (Celexa), sertraline (Zoloft), fluvoxamine (Luvox), and escitalopram oxalate (Lexapro). SSRIs are commonly used as first-line treatment of depression and act by blocking the action of the 5-HTT serotonin transporter. Individuals with the S-allele produce lower levels of the SSRI target (the serotonin transporter); hence often have a diminished or delayed response. Individuals homozygous for the L-allele are more likely to respond well to SSRIs (within 3 – 4 weeks). However, individuals with the S-allele may have a delayed response to SSRI antidepressants and may require a longer treatment period before any benefits are observed. Some individuals with the S-allele may not experience any noticeable benefits from SSRI medications, even after an extended treatment period. Alternative antidepressants may be recommended for patients carrying the S-allele.

A simple DNA test can be completed to determine which form of the SLC6A4 gene a person has inherited. The test determines the length of the 5-HTTLPR in the SLC6A4 gene and distinguishes between the S-allele (which occurs due to a deletion) and the L-allele.

People with two copies of the S-allele are more likely to be unhappy and will pass this form of the SLC6A4 gene to all of their children. People with two copies of the L-allele, have a decreased risk of unhappiness and depression. Heterozygotes have one copy of the L-allele and one copy of the S-allele. Having one copy of the S-allele also impacts the level of happiness and these individuals have a 50% chance of passing the S-allele to their children.

• Pezawas L et al. (2005). 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nature Neuroscience 8: 828-834.

• Zhao Q et al. (2016). Association between anxiety-depression and 5-HTTLPR gene polymorphism in school-aged twins. CJCP, 18(1): 61-66.

• Huezo-Diaz P et al. (2009). Moderation of antidepressant response by the serotonin transporter gene. Br J Psychiatry 195(1): 30-38.

• Serretti A et al. (2007). Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry 12: 247-257.