Selection in the dopamine receptor 2 gene: a candidate SNP study

Abstract

Dopamine is a major neurotransmitter in the human brain and is associated with various diseases. Schizophrenia, for example, is treated by blocking the dopamine receptors type 2. Shaner, Miller & Mintz (2004) stated that schizophrenia was the low fitness variant of a highly variable mental trait. We therefore explore whether the dopamine receptor 2 gene (DRD2) underwent any selection processes. We acquired genotype data of the 1,000 Genomes project (phase I), which contains 1,093 individuals from 14 populations. We included single nucleotide polymorphisms (SNPs) with two minor allele frequencies (MAFs) in the analysis: MAF over 0.05 and over 0.01. This is equivalent to 151 SNPs (MAF > 0.05) and 246 SNPs (MAF > 0.01) for DRD2. We used two different approaches (an outlier approach and a Bayesian approach) to detect loci under selection. The combined results of both approaches yielded nine (MAF > 0.05) and two candidate SNPs (MAF > 0.01), under balancing selection. We also found weak signs for directional selection on DRD2, but in our opinion these were too weak to draw any final conclusions on directional selection in DRD2. All candidates for balancing selection are in the intronic region of the gene and only one (rs12574471) has been mentioned in the literature. Two of our candidate SNPs are located in specific regions of the gene: rs80215768 lies within a promoter flanking region and rs74751335 lies within a transcription factor binding site. We strongly encourage research on our candidate SNPs and their possible effects.

Keywords: DRD2; Dopamine; Dopamine receptor 2; Schizophrenia; Selection.

Figure 1. Location of candidate SNPs under balancing selection in DRD2.

E1-8 are exons 1 to 8. (1) rs60599314, (2) rs79549222, (3) rs12574471, (4) rs80215768, (5) rs76581995, (6) rs80014933, (7) rs74751335, (8) rs77264605, (9) rs76499333.

Figure 2. Detection of outlier SNPs of the DRD2 gene using FDIST (LOSITAN).

X-axis: estimated heterozygosity values. Y-axis: F_ST-values. The upper area indicates positive directional selection, the middle area neutrality, and the lower area balancing selection. Confidence intervals represent borders between “selection areas”. See Table S2 for the exact results on the SNPs.

Figure 3. Graphical output of BayeScan.

X-axis: log10(q values) for all SNPs, the threshold is −2. Y-axis: F_ST-values, where high values indicate directional selection, low values balancing selection. For exact results see Table S2. Squares: the nine SNPs in the MAF > 0.05 sample that BayeScan and LOSITAN find.