Association between common variation in genes encoding sweet taste signaling components and human sucrose perception

Abstract

Variation in taste perception of different chemical substances is a well-known phenomenon in both humans and animals. Recent advances in the understanding of sweet taste signaling have identified a number of proteins involved in this signal transduction. We evaluated the hypothesis that sequence variations occurring in genes encoding taste signaling molecules can influence sweet taste perception in humans. Our population consisted of unrelated individuals (n = 160) of Caucasian, African-American, and Asian descent. Threshold and suprathreshold sensitivities of participants for sucrose were estimated using a sorting test and signal detection analysis that produced cumulative R-index area under the curve (AUC) scores. Genetic association analysis revealed significant correlation of sucrose AUC scores with genetic variation occurring in the GNAT3 gene (single point P = 10(-3) to 10(-4)), which encodes the taste-specific G(alpha) protein subunit gustducin. Subsequent sequencing identified additional GNAT3 variations having significant association with sucrose AUC scores. Collectively, GNAT3 polymorphisms explain 13% of the variation in sucrose perception. Our findings underscore the importance of common genetic variants influencing human taste perception.

Figure 1

The results of single-SNP association analysis. (A) Cumulative R_c-indices of 2 subjects plotted as a function of sucrose concentrations. Gray inverted triangles, subject with perfect discrimination abilities; red triangles, subject with low discrimination abilities. The vertical axis is the cumulative R-index, the horizontal axis shows sucrose concentration intervals. (B–H) Association results for SNPs from 7 candidate gene loci (indicated on the top of each graph). Statistical significance of SNPs at each locus is shown on the −log (P) scale as a function of chromosomal position (NCBI build 36). Genotyped SNPs at each locus are shown in red rhombs. Imputed SNPs indicated by blue triangles. Bottom panel shows genes at each locus as annotated in the University of California–San Cruz Genome Browser Annotation Database as of 16 December 2008. (I) Quantile–quantile plot of tails of the P value distribution for the sucrose AUC scores. Scatter plot of the observed ordered −log P values versus the −log expected ordered P values under the complete null. Dashed lines and gray area indicate the 0.025 and 0.975 pointwise quantiles of the ordered P value under the complete null distribution. The percentiles depicted with dashed lines were calculated using a beta approximation for the distribution of ordered statistics of uniform variates and assuming independence across tests. The gray area was obtained with 1000 permutations. The plot in red is for the P values for all genotyped SNPs, whereas the plot in black is for P values excluding all SNPs within the GNAT3 region.

Figure 2

Box–Whisker plots showing the distributions of AUC scores among genotypic groups of the 14 significant SNPs (indicated above each plot). Genotypes are listed at the bottom of each plot. Empty bars correspond to 25% and 75% percentiles and vertical lines outside of the bars indicate value range. Black lines inside of bars are statistical medians. Asterisks indicate outliers. Circles show rare observations. Vertical axis is the AUC score.

Figure 3

The results of single-SNP association analyses for chromosomal region 7q. Statistical significance values of SNPs are shown on the −log (P) scale as a function of chromosomal position (NCBI build 36). Genotyped SNPs are shown in red rhombs. Imputed SNPs indicated by colored triangles. Genes and the position of exons, as well as the direction of transcription, are noted below the plot (data from University of California–Santa Cruz genome browser). The most significant SNPs are green diamonds. Estimated recombination rate is plotted in cyan to reflect the local LD structure (data from HapMap).

Figure 4

The results of haplotype association analysis. (A) A graphical presentation of the LD block structure of a 79-kb region across the 7q21 (79.925–80.004 Mb) in Caucasian and Asian sample populations and in 4 HapMap populations (indicated on the left). Individual LD blocks are in gray and yellow. The bottom plot shows the locations of the GNAT3 exons and introns. The positions of 15 significant SNPs identified in this study are indicated by red lines below their rs numbers. (B) Allele frequencies of significant SNPs in 4 HapMap populations (indicated on the left). Individual alleles are represented by colored rectangles. The heights of 2 rectangles indicate relative allele frequencies in population. Red, allele associated with high AUC scores; blue, allele associated with low AUC scores. (C) Median-joining network of 4 haplotypes, color coded according to regions of origin. Haplotypes are indicated by numbers 1–4. The sizes of colored circles correspond to the frequency of haplotype in the entire population (also indicated on the top of each circle). Tag SNPs used for haplotype inference are also indicated. (D) Box–Whisker plots demonstrate distributions of AUC scores as a function of haplotype combinations. Haplotype combinations are indicated on the bottom of the plot. Upper scheme indicates presence of high- (red) and low (blue)-sensitivity alleles in the particular haplotypes. Number of subjects with particular haplotype combinations (n) is also indicated on the top. Empty bars correspond to 25% and 75% percentiles and vertical lines outside of the bars indicate value range. Red lines inside of bars are statistical medians. Asterisks indicate outliers. Circles show rare observations. Vertical axis is the AUC score. (E) The fraction of genetic variance explained by 4 haplotypes. Vertical log axis is a coefficient of determination (regression R²). Haplotypes are indicted on the bottom.

Figure 5

Matrix plot demonstrating the results of SNP-SNP association SNP-SNP interaction analyses. Upper triangle shows P values of association for pairwise combinations of significant GNAT3 SNPs. Each square represents the magnitude of P value for a single pair of markers, with a red color indicating highest level of significance and white color indicating lowest level of significance (scale on the right). The squares on the medial diagonal correspond to P values of a single-SNP association analysis. Lower triangle shows probability of interactions between significant SNPs. Each square represents the magnitude of P value for a pair of markers, with a green color indicating highest level of significance and white color indicating lowest level of significance (scale on the bottom).