Absolute pitch exhibits phenotypic and genetic overlap with synesthesia

Abstract

Absolute pitch (AP) and synesthesia are two uncommon cognitive traits that reflect increased neuronal connectivity and have been anecdotally reported to occur together in an individual. Here we systematically evaluate the occurrence of synesthesia in a population of 768 subjects with documented AP. Out of these 768 subjects, 151 (20.1%) reported synesthesia, most commonly with color. These self-reports of synesthesia were validated in a subset of 21 study subjects, using an established methodology. We further carried out combined linkage analysis of 53 multiplex families with AP and 36 multiplex families with synesthesia. We observed a peak NPL LOD = 4.68 on chromosome 6q, as well as evidence of linkage on chromosome 2, using a dominant model. These data establish the close phenotypic and genetic relationship between AP and synesthesia. The chromosome 6 linkage region contains 73 genes; several leading candidate genes involved in neurodevelopment were investigated by exon resequencing. However, further studies will be required to definitively establish the identity of the causative gene(s) in the region.

Figure 1.

The genome-wide linkage plots are shown for AP (upper plot, n = 53 families) and for synesthesia (middle plot, n = 36 families). The lower plot shows the combined linkage analysis with both AP and synesthesia families. In our AP families, 126 subjects with documented AP were genotyped, and of these, 28 (22%) report the presence of synesthesia in addition to AP. Likewise, among the 36 families with synesthesia, 8 families (22%) include subjects who report the presence of AP, although these individuals have not been formally tested for the AP phenotype. The full family trees are given in Supplementary Material, Figure S2. Analysis of linkage was carried out using the NPL-exp option in MERLIN. LOD scores are shown on the Y-axis, and genome-wide position (in cM) is given on the X-axis, with chromosomes as indicated. A maximum NPL-exp LOD score of 4.68 is achieved on chromosome 6q in the combined analysis. The dotted lines indicate LOD = 2 in each plot. The solid lines indicate LOD = 3 and/or LOD = 4 (lower plot).

Figure 2.

Details of linkage plots (NPL-exp) on chromosome 6 for AP (open circles), synesthesia (closed triangles) and combined AP and synesthesia (solid line). The extent of the linkage region we have considered for investigation of candidate genes is indicated by the dashed arrows.

Figure 3.

Details of linkage plots on chromosome 2 for AP (open circles), synesthesia (closed triangles) and combined AP and synesthesia (solid line). The left panel shows results using the NPL-exp option in MERLIN. The right panel shows results using a dominant model with penetrance set at 0.9. Note that in addition to two prominent peaks (HLOD > 4) in the combined analysis, a linkage peak of HLOD = 3.93 is also observed for AP families alone.