In the forensic genetic genealogy world, the 23andMe database is well-known and well-loved for its ability to provide leads, especially on cold case John/Jane Does and sexual assaults.
Now, researchers at 23andMe have utilized the expansive database of over 12 million individuals to identify a genetic risk factor associated with the loss of smell after a COVID-19 infection—a long-haul symptom that affects as many as 1.6 million people six months after contracting the virus.
“[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.
The genome-wide association, published as a brief in Nature Genetics earlier this week, is based on 69,841 SARS-CoV-2 test-positive individuals who self-reported their symptoms. The 23andMe 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.
Inputting that data into a logistic regression model predicting loss of smell or taste as a function of age, sex and genetic ancestry, the research team found that individuals of East Asian or African American ancestry were significantly less likely to report loss of smell/taste compared with individuals of European ancestry.
The research team then conducted a genome-wide association study within each ancestry group separately (total sample size = 56,373) before performing a multi-ancestry meta-analysis using a fixed effects model. The model 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.
Calling on the extensive database again, the researchers’ next step was 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.
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.”