Why Can the Same Fragrance Smell Stronger to Different People?

When people smell the same fragrance material, some find it very strong while others do not. Part of that difference is linked to how odor receptors in the nose function.

A 2019 study compared genetic variation and odor ratings in 332 people, then examined the receptors in cells. It found examples in which variation in just one receptor was associated with the intensity or pleasantness of a particular odor. The study explored the roles of individual receptors in a sense of smell that depends on many receptors working together.

Using differences between people to investigate the nose

Humans have about 400 potentially functional olfactory receptors, and a single odorant can stimulate several of them. If one receptor responds weakly, do other receptors compensate so that perception remains unchanged? Or do particular receptors carry important information? These questions motivated the study.

The genes encoding receptors naturally differ in sequence from person to person. The researchers used these variations to investigate how receptor responses connect to perceptions such as intensity and pleasantness. A distinctive feature was the use of cell experiments to explore the mechanisms behind the observed individual differences.

Comparing genes in 332 people with 276 olfactory measures

The underlying psychophysical experiment involved 391 people, who rated the intensity and pleasantness of 66 odors at two concentrations, plus two solvents, on seven-point scales. Each stimulus was rated twice. For analysis, scores were converted to ranks within each person’s ratings to reduce the influence of individual differences in scale use.

For 332 of those participants, the researchers analyzed regions encompassing 418 olfactory receptor genes. They examined associations with 276 measures in total: intensity and pleasantness at each concentration, detection thresholds indicating how dilute three substances could become while remaining detectable, and overall olfactory ability. Age, sex, and components related to genetic ancestry were also included in the analyses.

Testing many combinations increases the likelihood of chance associations. After correction for multiple comparisons, significant associations with a locus containing a single receptor remained for eight perceptual measures. The strongest associations involved intensity more often than pleasantness.

A genetic association alone does not identify the receptor

When genes lie close together on a chromosome, their sequence variants are more likely to be inherited together. A strong statistical association with a gene does not necessarily mean that its receptor actually responds to the odor.

A clear example is 2-ethylfenchol. Its perceived intensity was associated with variation in three neighboring receptor genes, OR11A1, OR12D2, and OR10C1. Statistically, a variant in OR10C1 showed the strongest association.

However, when the researchers expressed the major sequence variants in cells and measured their responses, OR11A1 was the receptor that responded in this assay. Moreover, OR11A1 variants with weaker responses in cells corresponded to lower intensity ratings in people. Combining human associations with cellular responses helped narrow down the candidate receptor involved.

Weaker receptors often meant weaker perceived odor, but not always

The cell-based work drew not only on associations that met the strict statistical threshold but on the top 50 associations in a broader exploratory set. After accounting for overlapping regions and related issues, the researchers tested 36 locus–odor combinations and identified 14 responsive receptors.

Ultimately, differences in receptor function measured in cells corresponded to human intensity or pleasantness ratings for 10 receptor–odor combinations. Three confirmed earlier findings and seven were new. These 10 examples come from a different validation stage than the eight measures surviving the initial multiple-comparison correction.

In eight of the 10 cases, carrying a lower-functioning receptor variant was associated with perceiving a weaker odor. However, there were also cases in which weaker responses were associated with greater perceived intensity, or with changes in pleasantness.

For linalool, for example, reduced OR1C1 responses corresponded to lower intensity ratings, whereas reduced OR2A25 responses corresponded to higher ratings. Even for the same substance, the direction of the relationship differed according to the receptor. Pleasantness could also either increase or decrease with reduced receptor function.

The strength of the associations also varied with odor concentration. This is consistent with the idea that different combinations of receptors participate at low and high concentrations. For the detection thresholds of the three substances tested, however, no single-receptor association was strong enough to proceed to cellular validation. The ability to notice a very dilute odor needs to be distinguished from how strong an odor seems when it is clearly present.

How much individual variation could be explained?

The researchers also examined how much variation in each measure could be explained by four factors: variation in the most strongly associated single receptor, components related to genetic ancestry, age, and sex.

These factors explained 10–20% of the variation in 15 measures, but the median across all 276 measures was 4.77%. The proportion differed by substance and measurement; this was not a finding that one receptor variant determines a person’s preferences. Nor is this percentage the heritability of smell overall or the accuracy of predicting an individual’s preferences.

Associations with ancestry-related components were also observed, but the authors noted that these data could not separate genetic effects from potentially overlapping cultural and social experience. Nor did they find a simple overall relationship in which people who were more genetically similar also perceived odors more similarly overall.

What emerges from moving between human noses and cultured cells?

The study did not replicate its associations in a separate group of participants. The cell experiments provided additional evidence, but the assay system did not reproduce every feature of the nose, such as mucus or mechanisms that transport and transform odor molecules.

Indeed, in some cases with strong human genetic associations, the researchers could not identify a responding receptor in cells. One example was diacetyl: modifying OR6Y1 with reference to sequences from other animals produced a response, providing support for this candidate. This illustrates why a lack of response in cells should not automatically be interpreted as irrelevance in the nose.

Summary

Even in a sense of smell that combines many receptors, functional variation in one particular receptor was shown to relate to odor intensity or pleasantness. In eight of the 10 cases linking function with perception, lower-response variants were associated with lower intensity ratings. But there were exceptions, such as linalool, where the direction differed between receptors.

Furthermore, the amount of individual variation explained differed between measures, even after including age and other factors. The study offers a concrete starting point in nasal receptors for understanding why the same fragrance material can smell different to different people, while also encouraging consideration of concentration, multiple receptors, and experience.

The study was supported by the US NIH, the São Paulo Research Foundation, and other sources. The paper disclosed that coauthor J. D. Mainland was serving on Aromyx’s scientific advisory board and receiving compensation for that work.

Reference

Trimmer C, et al. (2019). Genetic variation across the human olfactory receptor repertoire alters odor perception. PNAS, 116(19), 9475–9480. Original paper.