Six months after contracting COVID-19, as many as 1.6 million people in the United States are still unable to smell or taste, or have at least experienced a change in their ability to smell/taste. Despite this large number, the underlying mechanism of COVID-19-associated smell/taste loss is unclear.
However, a new discovery published as a brief in Nature Genetics has moved the needle, identifying a genetic link to the biological mechanisms.
The genome-wide association study by researchers at 23andMe is based on 69,841 SARS-CoV-2 test-positive individuals who self-reported their symptoms. The researchers contrasted the 68% (47,298) of participants who reported loss of smell or taste with the 32% SARS-CoV-2 positive individuals who did not report such a symptom.
In a multi-ancestry meta-analysis using a fixed effects model, the research team identified a single locus of interest at chr4q13.3. The index single nucleotide polymorphisms (SNP) at this locus was rs7688383. Interestingly, no other locus achieved genome-wide significance in the multi-ancestry meta-analysis or in any of the input populations.
The researchers then conducted a phenome-wide association study across approximately 1,300 phenotypes defined in the 23andMe database. They identified four associated phenotypes—two are related to the ability to smell, one is related to ice cream taste preference and one is related to tobacco use.
Once inputted into a regional plot, the team uncovered four genes within 150 kb of chr4q13.3—UGT2A1, UGT2A2, UGT2B4, SULT1B1. rs7688383, the index variant itself, was actually plotted within an intron of the overlapping UGT2A1 and UGT2A2 genes. Not only were those two genes the closest, but they were also the most biologically plausible as they are expressed in the olfactory epithelium.
According to the study, UGT2A1 and UGT2A2 are part of a family of enzymes that metabolize lipophilic substrates through conjugation with glucoronic acid. Animal studies have shown that during olfaction, these enzymes are involved in the elimination of the odorants that enter the nasal cavity and bind to olfactory receptors.
“For example, glucuronidation of odorants fails to stimulate the olfactory bulb, which prevents the odor from being detected by the brain, functionally demonstrating the effect of the enzyme produced by these genes on the odorant. This results in the clearance of the odorant to facilitate the transient experience of olfaction, once the stimuli are no longer present in the environment,” the research team explains in their brief, published on Monday.
Recent evidence suggests that SARS-CoV-2 enters and accumulates in olfactory support cells, which are metabolically and functionally associated with olfactory neurons and odorant signal transduction. Previous literature has proposed that olfactory sensation is impaired when these essential functions are disrupted.
How UGT2A1 and UGT2A2 are involved in this process is still unclear but given their localization and essential function, the researchers conclude the genes “may play a role in the physiology of infected cells and the resulting functional impairment that contributes to loss of ability to smell.”
“[The study is] this really beautiful example of science where, starting with a large body of activated research participants who have done this 23andMe test, we were able to very quickly gain some biological insights into this disease that would otherwise be very, very difficult to do,” Adam Auton, vice president of human genetics at 23andMe and the lead author of the study, told NBCNews.