Genetic variation in a human odorant receptor alters odour perception

Human olfactory perception differs enormously between individuals, with large reported perceptual variations in the intensity and pleasantness of a given odour. Androstenone (5α-androst-16-en-3-one), an odorous steroid derived from testosterone, is variously perceived by different individuals as offensive ("sweaty, urinous"), pleasant ("sweet, floral"), or odourless 1-3. Up to 30% of humans have reduced sensitivity to androstenone, with 6% fitting the criteria of specific anosmia or "odour blindness" to androstenone, which may be a genetically determined trait 1,3,4. The mechanistic basis of this phenomenon is unknown, but it has been hypothesized that genetic variation in odorant receptors 5-7 may account for interindividual variation in odour perception 1,4,8. Here we show that a human odorant receptor, OR7D4, is selectively activated in vitro by androstenone and the related odorous steroid androstadienone (androsta-4,16-dien-3-one) and does not respond to a panel of 64 other odours and two solvents. A common variant of this receptor (OR7D4 WM) contains two non-synonymous single nucleotide polymorphisms (SNPs), resulting in two amino acid substitutions (R88W, T133M) and severely impaired function in vitro. Human subjects with RT/WM or WM/WM genotypes are less sensitive to androstenone and androstadienone and find both odours less unpleasant than subjects with the functional RT/RT genotype. A second variant with reduced function in vitro, OR7D4 P79L, also results in reduced sensitivity to androstenone in human subjects. OR7D4 S84N, a variant with increased function in vitro, was found in several subjects who showed increased sensitivity to androstenone and androstadienone. We conclude that polymorphisms in OR7D4 contribute to the variability in perception of these steroidal odours, which have been suggested to act as modulatory pheromones in humans 9-11. Our results demonstrate the first link between the function of an odorant receptor in vitro and odour perception, establishing the basis for the unravelling of olfactory coding in humans.