A genetic variant near olfactory receptor genes influences cilantro preference

The Coriandrum sativum plant has been cultivated since at least the second millennium BCE[1]. Its fruits (commonly called coriander seeds) and leaves (called cilantro or coriander) are important components of many cuisines. In particular, South Asian cuisines use both the leaves and the seeds prominently, and Latin American food often incorporates the leaves.

The desirability of cilantro has been debated for centuries. Pliny claimed that coriander had important medicinal properties: ‘vis magna ad refrigerandos ardores viridi’ (‘while green, it is possessed of very cooling and refreshing properties’)[2]. The Romans used the leaves and seeds in many dishes, including moretum (a herb, cheese, and garlic spread similar to today’s pesto)[3]; the Mandarin word for cilantro, (xiāngcài), literally means ‘fragrant greens.’ However, the leaves in particular have long inspired passionate hatred as well, e.g., John Gerard called it a ‘very stinking herbe’ with leaves of ‘venemous quality’[4, 5].

It is not known why cilantro is so differentially perceived. The proportion of people who dislike cilantro varies widely by ancestry[6]; however, it is not clear to what extent this may be explained by differences in environmental factors, such as frequency of exposure. In a twin study, the heritability of cilantro dislike has been estimated as 0.38 (confidence interval (CI) 0.22–0.52) for odor and 0.52 (CI 0.38–0.63) for flavor[7].

The smell of cilantro is often described as pungent or soapy. It is suspected, although not proven, that cilantro dislike is largely driven by the odor rather than the taste. The key aroma components in cilantro consist of various aldehydes, in particular (E)-2-alkenals and n-aldehydes[8, 9]. The unsaturated aldehydes (mostly decanal and dodecanal) in cilantro are described as fruity, green, and pungent; the (E)-2-alkenals (mostly (E)-2-decenal and (E)-2-dodecenal) as soapy, fatty, ‘like cilantro,’ or pungent[8, 9].

Several families of genes are important for taste and smell. The TAS1R and TAS2R families form sweet, umami, and bitter taste receptors[10, 11]. The olfactory receptor family contains about 400 functional genes in the human genome. Each receptor binds to a set of chemicals, enabling one to recognize specific odorants or tastants. Genetic differences in many of these receptors are known to play a role in how we perceive tastes and smells[12–15].

Here, we report on a genome-wide association study (GWAS) of cilantro soapy-taste detection. Briefly, the GWAS was conducted in 14,604 unrelated participants of primarily European ancestry who responded to an online questionnaire asking whether they thought cilantro tasted like soap (Table1). Two single-nucleotide polymorphisms (SNPs) were genome-wide significant (p < 5 × 10⁻⁸) in this population. One SNP, in a cluster of olfactory receptors, replicated in a non-overlapping group of 11,851 participants (again, unrelated and of primarily European ancestry) who reported whether they liked or disliked cilantro (see the ‘Methods’ section for full details). Figure1 shows p values across the whole genome; Figure2 shows p values near the most significant associations. A quantile-quantile plot (Additional file1) shows little (λ = 1.007) global inflation of p values. Index SNPs with p values under 10⁻⁶ are shown in Table2 (along with replication p values); all SNPs with p values under 10⁻⁴ are shown in Additional file2.

	N	Proportion female	Age (SD)
Tastes soapy	1,994	0.566	49.0 (15.0)
Does not taste soapy	12,610	0.489	48.3 (15.2)
Total	14,604	0.500	48.4 (15.2)
Dislikes cilantro	3,181	0.487	47.1 (16.6)
Likes cilantro	8,906	0.420	43.8 (14.5)
Total	12,087	0.438	44.7 (15.1)

We found one significant association for cilantro soapy-taste that was confirmed in the cilantro preference population. The SNP rs72921001 (p_discovery = 6.4 × 10⁻⁹, odds ratio (OR) = 0.81, p_repl = 0.0057) lies on chromosome 11 within a cluster of eight olfactory receptor genes: OR2AG2, OR2AG1, OR6A2, OR10A5, OR10A2, OR10A4, OR2D2, and OR2D3. The C allele is associated with both detecting a soapy smell and disliking cilantro. Of the olfactory receptors encoded in this region, OR6A2 appears to be the most promising candidate underlying the association with cilantro odor detection. It is one of the most studied olfactory receptors (often as the homologous olfactory receptor I7 in rats)[16–19]. A wide range of odorants have been found to activate this receptor, all of which are aldehydes[17]. Among the unsaturated aldehydes, octanal binds best to rat I7[18]; however, compounds ranging from heptanal to undecanal also bind to this receptor[17]. Several singly unsaturated n-aldehydes also show high affinity, including (E)-2-decenal[17]. These aldehydes include several of those playing a key role in cilantro aroma, such as decanal and (E)-2-decenal. Thus, this gene is particularly interesting as a candidate for cilantro odor detection. The index SNP is also in high LD (r² > 0.9) with three non-synonymous SNPs in OR10A2, namely rs3930075, rs10839631, and rs7926083 (H43R, H207R, and K258T, respectively). Thus, OR10A2 may also be a reasonable candidate gene in this region.

The second significant association, with rs78503206 (p_discovery = 3.2 × 10⁻⁸, OR = 0.68, p_repl = 0.49), lies in an intron of the gene SNX9 (sorting nexin-9; see Figure2). SNX9 encodes a multifunctional protein involved in intracellular trafficking and membrane remodeling during endocytosis[20]. It has no known function in taste or smell and did not show association with liking cilantro in the replication population. This SNP is located about 80 kb upstream of SYNJ2, an inositol 5-phosphatase thought to be involved in membrane trafficking and signal transduction pathways. In candidate gene studies, SYNJ2 SNPs were found to be associated with agreeableness and symptoms of depression in the elderly[21] and with cognitive abilities[22]. In mice, a Synj2 mutation causes recessive non-syndromic hearing loss[23]. Given recent evidence that the perception of flavor may be influenced by multiple sensory inputs (cf.[24, 25]), we cannot exclude the SYNJ2-linked SNP as conveying a biologically meaningful association. While this SNP may be a false positive, it could also be the case that this SNP is associated only with detecting a soapy smell in cilantro (and not in liking cilantro). In addition, we were unable to replicate the SNPs that were found to be nominally significant for cilantro dislike in[26] (we saw p values in the GWAS of 0.53, 0.41, and 0.53 for rs11988795, rs1524600, and rs10772397, respectively).

We have used two slightly different phenotypes in our discovery and replication, soapy-taste detection and cilantro preference, which are correlated (r² ≈ 0.33). Detection of a soapy taste is reportedly one of the major reasons people seem to dislike cilantro. Despite having over 10,000 more people reporting cilantro preference, we have used soapy-taste detection as our primary phenotype because it is probably influenced by fewer environmental factors. Indeed, we see a stronger effect of rs72921001 on soapy-taste detection than on cilantro preference (OR of 0.81 versus 0.92). A GWAS on the replication set gave no genome-wide significant associations. SNPs with p values under 10⁻⁶ for this analysis are shown in Additional file3.

We calculated the heritability for cilantro soapy-taste detection using the GCTA software[27]. We found a low heritability of 0.087 (p = 0.08, 95% CI −0.037 to 0.211). This estimate is a lower bound for the true heritability, as our estimate only takes into account heritability due to SNPs genotyped in this study. While this calculation does not exclude a heritability of zero, the existence of the association with rs72921001 does give a non-zero lower bound on the heritability. Despite the strength of the association of the SNP near OR6A2, it explains only about 0.5% of the variance in perceiving that cilantro tastes soapy. Our heritability estimate is lower than those given in a recent twin study (0.38 for odor and 0.52 for flavor)[7]. This could be due to the differences in phenotypes measured between the two studies, or it could be possible that other genetic factors not detected here could influence cilantro preference. For example, there could be rare variants not typed in this study (possibly in partial linkage disequilibrium with rs72921001) that have a larger effect on cilantro preference. Such rare variants could cause the true heritability of this phenotype to be larger than we have calculated. For example, the heritability of height is estimated to be about 0.8; however, the heritability tagged by common SNPs is calculated at about 0.45[26]. We note that there can be epigenetic modifiers of taste as well, for example, food preferences can even be transmitted to the fetus in utero through the mother’s diet[24].

Survey responses, while very efficient for collecting large amounts of data, can only approximately measure the detection and/or perception of the chemicals in cilantro. This has implications for the interpretation of our results. For example, it is possible that the SNP rs72921001 could have a large effect on detection of a specific chemical in cilantro, but that the resulting effect on liking cilantro is much weaker, being modulated by environmental factors. For example, many people might initially dislike cilantro yet later come to appreciate it. This environmental component could also be the reason that our heritability estimates are low. It would thus be interesting to study the genetics of cilantro taste/odor perception in a group without prior exposure to cilantro to reduce the environmental effect, using more direct measures of cilantro perception (i.e., having the subjects actually taste and smell cilantro).

Through a GWAS, we have shown that a SNP, rs72921001, near a cluster of olfactory receptors is significantly associated with detecting a soapy taste to cilantro. One of the genes near this SNP encodes an olfactory receptor, OR6A2, that detects the aldehydes that may make cilantro smell soapy and thus is a compelling candidate gene for the detection of the cilantro odors that give cilantro its divisive flavor.

We have shared full summary statistics for all SNPs with p values under 10⁻⁴ in Additional file2. Due to privacy concerns, under our IRB protocol, we are unable to openly share statistics for all SNPs analyzed in the study.