Gene Variant Linked to Worse Physical Symptoms, May Have Implications for AADC Deficiency, Study Suggests

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A genetic variant of DDC, the gene encoding L-aromatic amino acid decarboxylase (AADC), contributes to worse somatic symptoms due to low levels of serotonin — a neurotransmitter that contributes to well-being and happiness — in circulation, new research suggests.

The study, “A functional substitution in the L‐aromatic amino acid decarboxylase enzyme worsens somatic symptoms via a serotonergic pathway,” was published in the journal Annals of Neurology.

Somatic symptoms are physical symptoms like pain and fatigue, which can cause both emotional distress and difficulty functioning. Although such symptoms are often assessed in clinics, exactly how they work is still something of a mystery.

In this study, researchers questioned whether genetic variations might be linked to higher or lower measurements of somatic symptoms.

To find out, they first used a group of 1,607 people from a study involving jaw disorders. The group consisted of 165 jaw disorder cases and 1,442 controls. Participants were mostly female (58.7%) and white (55.3%).

Genetic data for this cohort was available, as were scores from the Pennebaker Inventory of Limbic Languidness (PILL), which is used to measure somatic symptoms. The researchers looked for genetic variants that were associated with higher PILL scores, and found a few.

Then, they used three other groups of patients — one from another jaw study, one from a mastectomy pain study, and one from a study involving several pain disorders — totaling an additional 3,189 people, to validate their findings. Like the discovery group, these groups were primarily composed of people who were white and female.

None of the genetic variants linked to PILL scores in the first group were consistently linked to PILL scores in all four of the groups tested. However, when the researchers combined the data on all the participants, they found that a variant in the DDC gene, called rs11575542, was significantly linked to higher PILL scores.

This variant results from the substitution of a single amino acid in the AADC protein. Using a combination of computer simulations and testing cells in dishes, the researchers determined this substitution hindered the protein’s function — namely the production of active serotonin and dopamine.

The researchers also analyzed serotonin levels and PILL scores in a small group of 77 patients. After excluding people on any kind of antidepressants that change serotonin levels, the investigators found that lower amounts of serotonin in the blood were associated with higher PILL scores. Although this doesn’t directly prove anything, it’s a data point that supports the idea that variations in DDC could affect somatic symptoms.

“We describe a molecular mechanism by which a minor allele in AADC lowers 5-HT [serotonin] plasma levels and thus possibly contributes to the emergence of somatic symptoms,” the researchers said.

“Targeting somatic symptoms by increasing the levels of serotonin using [antidepressants], for example, should be tested in individuals with high somatic scores, and carriers of minor allele of rs11575542 can be hypothesized to display the best response,” they added.

The findings may have implications for people with AADC deficiency, who exhibit symptoms captured by the PILL questionnaire, including sweating, nasal congestion, low blood sugar, and acid reflux.