Through what they claim is the largest genome-wide association study (GWAS) of olfactory genes, researchers in Iceland have identified genetic variants that affect how people perceive the strength and unpleasantness of fish odor. Many people find the smell of fish strong and unpleasant, but the new study—which involved more than 9,000 people in Iceland, and a sniff test—showed how some people carry a mutation in a particular gene that makes fish odor less intense. The researchers also identified other gene mutations that impact on the ability to discern the smell of licorice, and cinnamon.

“We discovered sequence variants that influence how we perceive and describe fish, licorice, and cinnamon odors,” said Rosa Gisladottir, PhD, from deCODE Genetics and the University of Iceland, who is first and co-corresponding author of the team’s published paper in Current Biology. “Since our sense of smell is very important for the perception of flavor, these variants likely influence whether we like food containing these odors.” Gisladottir and colleagues who are affiliated with universities in Iceland and in Sweden, reported on their findings in a paper titled, “Sequence Variants in TAAR5 and Other Loci Affect Human Odor Perception and Naming.”

Human olfaction is critical for a variety of functions and provides us with “a rich understanding of our social and physical environment,” the authors wrote. Researchers already know that our ability to perceive odors is achieved through olfactory receptors (OR) encoded by 855 olfactory receptor genes. However, about half of these genes in humans are thought to lack function, and are categorized as pseudogenes, leaving a relatively small repertoire of about 400 active olfactory receptor genes.

The reason for the loss of so many of these olfactory genes in humans has remained something of a mystery. “Although functional OR repertoires differ substantially between species, the inactivation of OR genes is particularly massive in the primate lineage for unknown reasons,” the team noted. “OR repertoires have shrunk during human evolution, as suggested by more loss-of-function variants in OR genes than any other gene class and unusually high sequence diversity in intact OR genes compared with other protein-coding genes.” What is also not well understood is how variation in the remaining active genes might influence differences in individuals’ senses of smell. “How does genetic sequence diversity in this unusual class of genes translate to perception and behavior?” the investigators asked.

Scent pens used in the smell test. [Jón Gústafsson, deCODE Genetics – Amgen Inc]
To explore this further, Gisladottir, together with co-corresponding deCODE author Kari Stefansson, and team, enlisted 9,122 Icelanders in a GWAS, in search of OR gene variants that influence odor perception. They asked the study participants to smell odors presented to them in pen-like devices that released a particular scent when uncapped. After the participant sniffed each odor pen, the researchers asked them to name the smell. Participants also rated the intensity and pleasantness of each smell. Odors tested included key ingredients found in licorice, cinnamon, fish, lemon, peppermint, and banana.

Through their analysis of genetic loci of interest, the team identified variants in that were linked with differences in the perception and naming of odors. They subsequently confirmed the findings in a separate cohort of 2,204 Icelanders. One of the variants implicated in odor perception was identified in a non-canonical olfactory receptor gene called trace amine-associated receptor 5 (TAAR5). The TAAR5 variant was found to affect the perception of a fish odor containing trimethylamine, a bacterial metabolite that is found in rotten and fermented fish, as well as in other animal odors and various bodily secretions.

In the smell tests, people with a particular variant of the TAAR5 gene were more likely either not to smell anything when presented with the fish odor, or to use descriptors for the smell that were neutral or positive, and not seafood related, such as “potatoes,” “caramel,” and “rose.” The findings are the first to show an important role for this gene in humans, the researchers said. “TAAR5 encodes a member of the TAAR family of trace amine-associated receptors, which are G protein-coupled receptors (GPCRs) that function as chemosensory receptors in the olfactory epithelium of vertebrates, detecting volatile and often aversive amines … To our knowledge, there are no prior reports of a sequence variant in TAAR5 that influences olfactory perception in humans.”

Gisladottir commented, “Carriers of the variant find the fish odor less intense, less unpleasant, and are less likely to name it accurately. There is a lot of animal research on TAAR5 in relation to its role in hard-wired aversive responses to trimethylamine. Our findings extend the implications of this research to human odor perception and behavior.”

A participant in the smell test. [Jón Gústafsson, deCODE Genetics – Amgen Inc]
The other two discoveries related to variants in more typical and common olfactory genes. These variants influenced an individual’s ability to name licorice and cinnamon odors. They also influenced the intensity and pleasantness associated with those odors. “We discovered a common variant in a cluster of olfactory receptors which is associated with increased sensitivity to trans-anethole, found in black licorice products but also in spices and plants such as anise seed, star anise, and fennel,” Gisladottir continued.

 

“Carriers of the variant find the licorice odor more intense, more pleasant, and can name it more accurately. Interestingly, the variant is much more common in East Asia than in Europe.” The cinnamon variant influenced the perception of trans-cinnamaldehyde, the major ingredient in both Chinese and Ceylon cinnamon. Carriers of this variant were able to name the cinnamon odor more accurately, the team reported. Carriers also found the odor more intense.

The combined findings indicate that variation in olfactory genes influences odor perception in humans. “Altogether, our results provide a unique window into the effects of sequence diversity on human olfaction,” the team concluded. “An individual’s personalized OR repertoire gives rise to myriad differences in perception and behavior, including olfactory language, which we are only beginning to understand.”

The newly reported results also show that, while humans have fewer olfactory genes compared to other species, some of the genetic variation that people do carry makes them more, rather than less, sensitive to particular smells such as licorice or cinnamon. “When coupled with evidence for geographical differences in allele frequencies, this raises the possibility that the portion of the extensive sequence diversity found in human olfactory receptor genes that affects our sense of smell is still being honed by natural selection,” the researchers suggested. They aim to continue to collect data on odor perception in people, and also plan to use the same olfactory tasks to investigate smell deficits in the context of COVID-19.

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