This post has an ambiguous SNPs, meaning it's unknown which allele is being referred to. Most of the SNPs have been flipped in their orientation.

Mechanism:

  • Less serotonin neuron firing and less postsynaptic receptors (SSRIs increase post-synaptic activation) (CC) (R).
  • The G allele (C allele in positive orientation) of the C-1019G (rs6295) polymorphism, which leads to higher expression of  5-HT1A  gene, is related to decreased comfort with close relationships (R).
  • Worse binding of serotonin to the 5HT1A receptor (C)...
  • Increased 5-HT1A autoreceptors in depressed subjects. Increasing 5-HT1A autoreceptor levels reduce serotonin neurotransmission (CC).

The C (minor) allele is associated with:

  • Impaired working memory in premenstrual phase (CC) (flipped allele orientation) (R).
  • In Asians, having 1 or 2 minor C alleles (CC or CG) reduced the likelihood of being in a romantic relationship. The C allele causes discomfort in close relationships with others (R). This may be because CC are more pessimistic and neurotic (in this study, the alleles are in negative orientation, we flipped them to positive) (R). 
  • Higher levels of "self-transcendence", a spiritual personality trait (R). 
  • Relatively less pain with a mild pain stimulus, but relatively more pain when exposed to more intense pain-stimulus (especially CC) (R).
  • Increased risk for depression, suicide, bipolar, schizophrenia and borderline personality disorder (R, R2, R3).
  • Increased risk of depression through the combination of 5-HT1A CC and BDNF CT or TT genotypes (R). 
  • Higher personality scores for Neuroticism and Harm Avoidance traits (R). 
  • Aggression and impulsivity. The CC genotype showed significantly higher impulsiveness scores compared to CG or GG carriers for various types of impulsiveness (R). 
  • Meta-analyses could not find any difference in antidepressant response with SSRIs (R).
  • No association of CC genotype with depressed or anxious mood. These results suggest that although the C-allele may promote higher expression of 5-HT1A autoreceptors, non-depressed subjects are able to compensate for the effect of the C allele, while depressed patients are not (R).
  • CC/CG (vs GG) had a significantly higher likelihood of ADHD (OR=2) (no flip) [R]

The G (major) allele is associated with:

  • Subjects carrying GG genotype showed significantly higher impulsiveness scores compared to GC or CC (no flip) (R)
  • 50.4% of individuals with the GG genotype and ~39.0% with CG/CC genotype in romantic relationships (R). 
  • 25% higher likelihood of being in a relationship (GG). Even after controlling for socioeconomic status, external appearance, religious beliefs, parenting style, and depressive symptoms, the difference was still significant. Love-related behaviors are associated with the serotonin levels in the brain. In animals, decreasing serotonin levels via 5-HT1A receptor activators (because it's working on autoreceptors) reduces female sexual receptivity and induces aggression towards male mates (R).

Technical: What the C Allele Does

The CC genotype is associated with increased 5-HT1A autoreceptors in depressed subjects. Increasing 5-HT1A autoreceptor levels reduce serotonin neurotransmission. Interestingly, studies in normal subjects have not found an association of the CC genotype with depressed or anxious mood. Furthermore, in normal subjects, although a trend for increased 5-HT1A autoreceptor levels with the CC genotype is observed, it was not statistically significant. These results suggest that although the C-allele may promote higher expression of 5-HT1A autoreceptors, normal subjects are able to compensate for the effect of the C allele, while depressed patients are not (R).

The C allele blocks the effects of a protein (transcription factor) Deaf1, which is important to produce the 5HT1A receptors….Deaf1 requires the G-allele to be functional (R).

The C-allele has opposite effects on the production of 5-HT1A receptors in serotonin-synthesizing neurons (i.e. raphe) compared to non-serotonin synthesizing neurons (R).

In serotonin synthesizing (raphe) neurons, Deaf1 represses 5-HT1A autoreceptors (which increases serotonin).  The C allele blocks this effect and leads to increased autoreceptors, which decreases the firing of serotonin neurons.

At the same time, in non-serotonin synthesizing neurons, it reduces postsynaptic 5HT1A receptors (because Deaf1 increases the 5HT1A receptors here), which also leads to less serotonin firing (R).

Bottom line: CC results in less firing of serotonin neurons.

rs6295

Parent Gene: HTR1A

Importance: 5
Less common allele: C = 45%
More common allele: G = 55%
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