The perception of quinine taste intensity is associated with common genetic variants in a bitter receptor cluster on chromosome 12

Abstract

The perceived taste intensities of quinine HCl, caffeine, sucrose octaacetate (SOA) and propylthiouracil (PROP) solutions were examined in 1457 twins and their siblings. Previous heritability modeling of these bitter stimuli indicated a common genetic factor for quinine, caffeine and SOA (22-28%), as well as separate specific genetic factors for PROP (72%) and quinine (15%). To identify the genes involved, we performed a genome-wide association study with the same sample as the modeling analysis, genotyped for approximately 610,000 single-nucleotide polymorphisms (SNPs). For caffeine and SOA, no SNP association reached a genome-wide statistical criterion. For PROP, the peak association was within TAS2R38 (rs713598, A49P, P = 1.6 × 10(-104)), which accounted for 45.9% of the trait variance. For quinine, the peak association was centered in a region that contains bitter receptor as well as salivary protein genes and explained 5.8% of the trait variance (TAS2R19, rs10772420, R299C, P = 1.8 × 10(-15)). We confirmed this association in a replication sample of twins of similar ancestry (P = 0.00001). The specific genetic factor for the perceived intensity of PROP was identified as the gene previously implicated in this trait (TAS2R38). For quinine, one or more bitter receptor or salivary proline-rich protein genes on chromosome 12 have alleles which affect its perception but tight linkage among very similar genes precludes the identification of a single causal genetic variant.

Figure 1.

Genome-wide association for PROP perception (A and B), followed by regional association between 7q34 variants and PROP perception (C) and LD among markers for the 7q34 region (D). (A) and (B) The observed –log 10 P-values by position (Mbp) for bitterness of PROP tasted in solution (A) and tasted within a saturated paper strip (B). The horizontal dotted gray lines show the genome-wide association significance level corrected for the 4.4 independent traits analyzed (calculated using http://gump.qimr.edu.au/general/daleN/matSpD/). The regional association plot between 7q34 variants and PROP perception (C) indicates the location of known genes. Bitterness of PROP tasted in solution is indicated using closed circles and tasted on a saturated paper strip is shown using open circles. (D) Heat-map of the LD in the 7q34 region. The second LD block captures the high LD within the region of peak association. Bitter receptor gene nomenclature has recently changed and gene alias are available online (http://www.ensembl.org/index.html).

Figure 2.

Genome-wide association for quinine perception (A), followed by regional association between 12p13.2 variants and quinine perception (B) and LD among markers for the 12p13.2 region (C). See Figure 1 for details.

Figure 3.

Average bitter taste intensity of quinine as rated by people from the discovery (top) and replication (bottom) samples grouped by their rs10772420 genotype. LMS, labeled magnitude scale; VAS, visual analogue scale. Values are means and confidence intervals corrected for family relationship (upper panel) or means and standard deviations (lower panel). The TAS2R19 A allele corresponds to the cysteine amino acid at position 299 and is associated with more intense perception of quinine in both samples.

Figure 4.

The Q–Q plots for each of the five substances analyzed. The 95% confidence interval is shown in gray. Values lifting above the quinine plot were from a single location on chromosome 12 within and near the TAS2R19 gene; most of these for PROP (in solution and PROP papers) centered on chromosome 7 within and near the TAS2R38 gene. The excess of SNPs with small P-values is low, and all λ values are near 1.0.