Creative Activities in Music--A Genome-Wide Linkage Analysis

Abstract

Creative activities in music represent a complex cognitive function of the human brain, whose biological basis is largely unknown. In order to elucidate the biological background of creative activities in music we performed genome-wide linkage and linkage disequilibrium (LD) scans in musically experienced individuals characterised for self-reported composing, arranging and non-music related creativity. The participants consisted of 474 individuals from 79 families, and 103 sporadic individuals. We found promising evidence for linkage at 16p12.1-q12.1 for arranging (LOD 2.75, 120 cases), 4q22.1 for composing (LOD 2.15, 103 cases) and Xp11.23 for non-music related creativity (LOD 2.50, 259 cases). Surprisingly, statistically significant evidence for linkage was found for the opposite phenotype of creative activity in music (neither composing nor arranging; NCNA) at 18q21 (LOD 3.09, 149 cases), which contains cadherin genes like CDH7 and CDH19. The locus at 4q22.1 overlaps the previously identified region of musical aptitude, music perception and performance giving further support for this region as a candidate region for broad range of music-related traits. The other regions at 18q21 and 16p12.1-q12.1 are also adjacent to the previously identified loci with musical aptitude. Pathway analysis of the genes suggestively associated with composing suggested an overrepresentation of the cerebellar long-term depression pathway (LTD), which is a cellular model for synaptic plasticity. The LTD also includes cadherins and AMPA receptors, whose component GSG1L was linked to arranging. These results suggest that molecular pathways linked to memory and learning via LTD affect music-related creative behaviour. Musical creativity is a complex phenotype where a common background with musicality and intelligence has been proposed. Here, we implicate genetic regions affecting music-related creative behaviour, which also include genes with neuropsychiatric associations. We also propose a common genetic background for music-related creative behaviour and musical abilities at chromosome 4.

Fig 1. Examples of the pedigrees in the study.

Arranging, composing and other creativity answers are shown for every individual; black denotes “yes” and white “no”. The question marks denote missing phenotypes. Individuals shown twice are linked with a coloured curve. Orange lines mark where the three most complex pedigrees (#13, #14 and #21) were split for the Merlin linkage analyses. The complexity is caused by the number of individuals and missing phenotypes in a pedigree. In some of the families, as in #14 and #41, music-related creative activities were common, whereas most of the families showed only a few individuals who arranged and/or composed music.

Fig 2. Merlin linkage results.

Multipoint linkage LOD scores for arranging (a), composing (c) NCNA (e) and other creativity (g). The chromosomal region around the best LOD score is depicted for each phenotype (b, d, f and h for arranging, composing, NCNA and other creativity, respectively). On the best regions, multipoint linkages are illustrated by curves (scale on the left) and the best joint linkage and LD results by points as negative logarithmic values (scale on the right). The X-scale shows positions as centimorgans.

Fig 3. Chromosome 4 linked region overlaps with our previous finding with musical aptitude.

Composing is linked to 4q22.1. In a previous article, the same region was found to be linked with KMT scores [35]. The linkage results are shown with solid lines, composing results on the LOD score scale (axis scale on the right) and KMT results as probability scores (scale on the left). The position information is shown in centimorgans.

Fig 4. Synaptic long-term depression pathway.

The LTD pathway was found to be overrepresented among genes suggestively associated with composing. This diagram shows the main molecules and their relationships that are involved in the LTD process. The climbing fibre originates from inferior olive and parallel fibres from the cerebellar cortex. There are various parallel fibres in contact with each Purkinje cell. Stimuli from climbing and parallel fibre impact Purkinje cell partially through the same receptors (mGluR and AMPAR). Parallel fibres function also through NO and GRID; the climbing fibre through CRFR1 and IGF1R. The climbing and parallel fibres are here shown side by side, but they may reside on different parts of the Purkinje cell. The pathway influences phosphorylation and internalization of AMPAR in parallel fibre, which in turn affects the synaptic function for future stimuli. The molecules and cascades related to genes that were suggestively associated with composing are lined with red (see Table 4).