How unpleasant people find the smell of fish may be influenced by an olfactory receptor gene variant they carry, a new genome-wide association study has found.

While there are more than 850 olfactory genes in the human genome, about half are thought to be nonfunctional due to a shrinking in the number of olfactory receptors in the primate and human lineages. However, there has also been an increase in sequence diversity among the remaining OR genes, suggesting a personalized suite of variants affects what people can smell and the intensity of those odors.

To explore the genetic basis of smell, researchers conducted a genome-wide association study of more than 9,000 individuals who underwent a smell test, sniffing samples of six different odors. As they reported on in the journal Current Biology, the researchers homed in on one variant in the TAAR5 gene that affects the perception of a fishy smell, but also a handful of variants influencing the perception of other smells.

"We discovered sequence variants that influence how we perceive and describe fish, licorice, and cinnamon odors," first author said in a statement. "Since our sense of smell is very important for the perception of flavor, these variants likely influence whether we like food containing these odors."

The authors conducted a GWAS of 9,122 Icelanders who completed a set of smell tasks. The participants smelled six odors — licorice, cinnamon, fish, lemon, peppermint, and banana — from the Sniffin' Sticks test of olfactory performance and were asked to name what they smelled and rate the intensity and pleasantness of the odor.

Overall, the fish smell was typically rated to be the least pleasant and peppermint was the one most often correctly identified. Also, as expected, intensity ratings of the odors decreased with age. 

The researchers identified variants in three loci that were associated with smell perception and naming. A missense variant in TAAR5 was associated with how intensely someone rated the fish odor, while three linked variants in OR6C70 and OR6C68 were tied to licorice intensity and rating, and a variant near an OR cluster on chromosome 11 was linked to the ability to name the cinnamon smell. These findings were subsequently validated in a separate set of 2,204 Icelanders.

In particular, the missense variant p.Ser95Pro in TAAR5, which encodes the trace amine-associated receptor 5, was linked to a decrease in the intensity rating of the fishy smell. That odor is largely due to the presence of trimethylamine, a bacterial metabolite found in rotten fish, animal odors, and human body secretions. Carriers also had increased problems naming the smell and had increased pleasantness ratings for the odor. They were also less likely to describe the smell by comparing it with typically foul-smelling items like "fermented skate" or "shark" and were more likely to describe it with neutral or pleasant terms like "potatoes," "ketchup," "caramel," or "rose."

In silico analysis predicts the p.Ser95Pro variant to be damaging to protein function, and the researchers noted that the location of this alteration in the receptor protein could affect a nearby highly conserved amino acid involved in TAAR1 and TAAR5 ligand interaction.

Based on the Genome Aggregation Database, the researchers noted that the frequency of the p.Ser95Pro variant varies by population, reaching a 2.2 percent frequency in Icelanders, 1.7 percent in Swedes, 0.8 percent in Southern Europeans, and 0.2 percent in Africans. The frequencies of the alleles affecting cinnamon and licorice perception also varied by population, suggesting that the human sense of smell may still be under natural selection.

https://www.cell.com/current-biology/fulltext/S0960-9822(20)31343-9

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