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

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.

Detecting signatures of positive selection associated with musical aptitude in the human genome.

Abilities related to musical aptitude appear to have a long history in human evolution. To elucidate the molecular and evolutionary background of musical aptitude, we compared genome-wide genotyping data (641 K SNPs) of 148 Finnish individuals characterized for musical aptitude. We assigned signatures of positive selection in a case-control setting using three selection methods: haploPS, XP-EHH and FST. Gene ontology classification revealed that the positive selection regions contained genes affecting inner-ear development. Additionally, literature survey has shown that several of the identified genes were known to be involved in auditory perception (e.g. GPR98, USH2A), cognition and memory (e.g. GRIN2B, IL1A, IL1B, RAPGEF5), reward mechanisms (RGS9), and song perception and production of songbirds (e.g. FOXP1, RGS9, GPR98, GRIN2B). Interestingly, genes related to inner-ear development and cognition were also detected in a previous genome-wide association study of musical aptitude. However, the candidate genes detected in this study were not reported earlier in studies of musical abilities. Identification of genes related to language development (FOXP1 and VLDLR) support the popular hypothesis that music and language share a common genetic and evolutionary background. The findings are consistent with the evolutionary conservation of genes related to auditory processes in other species and provide first empirical evidence for signatures of positive selection for abilities that contribute to musical aptitude.

The genome-wide landscape of copy number variations in the MUSGEN study provides evidence for a founder effect in the isolated Finnish population.

Here we characterized the genome-wide architecture of copy number variations (CNVs) in 286 healthy, unrelated Finnish individuals belonging to the MUSGEN study, where molecular background underlying musical aptitude and related traits are studied. By using Illumina HumanOmniExpress-12v.1.0 beadchip, we identified 5493 CNVs that were spread across 467 different cytogenetic regions, spanning a total size of 287.83 Mb (∼9.6% of the human genome). Merging the overlapping CNVs across samples resulted in 999 discrete copy number variable regions (CNVRs), of which ∼6.9% were putatively novel. The average number of CNVs per person was 20, whereas the average size of CNV per locus was 52.39 kb. Large CNVs (>1 Mb) were present in 4% of the samples. The proportion of homozygous deletions in this data set (∼12.4%) seemed to be higher when compared with three other populations. Interestingly, several CNVRs were significantly enriched in this sample set, whereas several others were totally depleted. For example, a CNVR at chr2p22.1 intersecting GALM was more common in this population (P=3.3706 × 10(-44)) than in African and other European populations. The enriched CNVRs, however, showed no significant association with music-related phenotypes. Moreover, the most common CNV locations in world's normal population cohorts (6q14.1, 11q11) were overrepresented in this population. Thus, the genome-wide CNV investigation in this Finnish sample set demonstrated features that are characteristic to isolated populations. Novel CNVRs and the functional implications of CNVs revealed in this study elucidate structural variation present in this population isolate, and may also serve as candidate gene loci for music-related traits.

Genome-wide copy number variation analysis in extended families and unrelated individuals characterized for musical aptitude and creativity in music.

Music perception and practice represent complex cognitive functions of the human brain. Recently, evidence for the molecular genetic background of music related phenotypes has been obtained. In order to further elucidate the molecular background of musical phenotypes we analyzed genome wide copy number variations (CNVs) in five extended pedigrees and in 172 unrelated subjects characterized for musical aptitude and creative functions in music. Musical aptitude was defined by combination of the scores of three music tests (COMB scores): auditory structuring ability, Seashores test for pitch and for time. Data on creativity in music (herein composing, improvising and/or arranging music) was surveyed using a web-based questionnaire.Several CNVRs containing genes that affect neurodevelopment, learning and memory were detected. A deletion at 5q31.1 covering the protocadherin-α gene cluster (Pcdha 1-9) was found co-segregating with low music test scores (COMB) in both sample sets. Pcdha is involved in neural migration, differentiation and synaptogenesis. Creativity in music was found to co-segregate with a duplication covering glucose mutarotase gene (GALM) at 2p22. GALM has influence on serotonin release and membrane trafficking of the human serotonin transporter. Interestingly, genes related to serotonergic systems have been shown to associate not only with psychiatric disorders but also with creativity and music perception. Both, Pcdha and GALM, are related to the serotonergic systems influencing cognitive and motor functions, important for music perception and practice. Finally, a 1.3 Mb duplication was identified in a subject with low COMB scores in the region previously linked with absolute pitch (AP) at 8q24. No differences in the CNV burden was detected among the high/low music test scores or creative/non-creative groups. In summary, CNVs and genes found in this study are related to cognitive functions. Our result suggests new candidate genes for music perception related traits and supports the previous results from AP study.

Could audiovisual training be used to improve cognition in extremely low birth weight children?

AIM: To study whether a dyslexia remediation programme, Audilex, improves cognition in extremely low birth (ELBW) children. METHODS: Six-year-old ELBW children were allocated to a 5-week training with Audilex or playing control computer games. Before and after intervention, auditory event-related brain potentials (ERP) to sound changes were recorded and reading related skills assessed. Primary outcome was the mismatch negativity (MMN) component of ERP. Secondary outcomes were Audilex Test (ability to perform the Audilex games), the reading skills after the intervention and 2 years later. Of eligible children, 39 (54%) consented and 22 (30%) completed the protocol. RESULTS: The MMN responses to the frequency (p = 0.02) and duration deviants (p < 0.01) increased after Audilex training (n = 11), but not after control game playing (n = 11). Audilex Test performance was similar in both groups. The reading skills were similar after intervention and 2 years later; word reading score 59.7, 66.8 and 74.9 and comprehensive reading score 8.1, 8.8 and 9.4 in Audilex, Control and healthy class-mate children, respectively. CONCLUSIONS: Although all children did not complete the protocol, the results suggest that training with Audilex dyslexia programme might be beneficial for enhancing neural-level sound discrimation and possibly reading skills in ELBW children. A larger trial is warranted.

Association of the arginine vasopressin receptor 1A (AVPR1A) haplotypes with listening to music.

Music is listened in all cultures. We hypothesize that willingness to produce and perceive sound and music is social communication that needs musical aptitude. Here, listening to music was surveyed using a web-based questionnaire and musical aptitude using the auditory structuring ability test (Karma Music test) and Carl Seashores tests for pitch and for time. Three highly polymorphic microsatellite markers (RS3, RS1 and AVR) of the arginine vasopressin receptor 1A (AVPR1A) gene, previously associated with social communication and attachment, were genotyped and analyzed in 31 Finnish families (n=437 members) using family-based association analysis. A positive association between the AVPR1A haplotype (RS1 and AVR) and active current listening to music (permuted P=0.0019) was observed. Other AVPR1A haplotype (RS3 and AVR) showed association with lifelong active listening to music (permuted P=0.0022). In addition to AVPR1A, two polymorphisms (5-HTTLPR and variable number of tandem repeat) of human serotonin transporter gene (SLC6A4), a candidate gene for many neuropsychiatric disorders and previously associated with emotional processing, were analyzed. No association between listening to music and the polymorphisms of SLC6A4 were detected. The results suggest that willingness to listen to music is related to neurobiological pathways affecting social affiliation and communication.

Musical aptitude is associated with AVPR1A-haplotypes.

Artistic creativity forms the basis of music culture and music industry. Composing, improvising and arranging music are complex creative functions of the human brain, which biological value remains unknown. We hypothesized that practicing music is social communication that needs musical aptitude and even creativity in music. In order to understand the neurobiological basis of music in human evolution and communication we analyzed polymorphisms of the arginine vasopressin receptor 1A (AVPR1A), serotonin transporter (SLC6A4), catecol-O-methyltranferase (COMT), dopamin receptor D2 (DRD2) and tyrosine hydroxylase 1 (TPH1), genes associated with social bonding and cognitive functions in 19 Finnish families (n = 343 members) with professional musicians and/or active amateurs. All family members were tested for musical aptitude using the auditory structuring ability test (Karma Music test; KMT) and Carl Seashores tests for pitch (SP) and for time (ST). Data on creativity in music (composing, improvising and/or arranging music) was surveyed using a web-based questionnaire. Here we show for the first time that creative functions in music have a strong genetic component (h(2) = .84; composing h(2) = .40; arranging h(2) = .46; improvising h(2) = .62) in Finnish multigenerational families. We also show that high music test scores are significantly associated with creative functions in music (p<.0001). We discovered an overall haplotype association with AVPR1A gene (markers RS1 and RS3) and KMT (p = 0.0008; corrected p = 0.00002), SP (p = 0.0261; corrected p = 0.0072) and combined music test scores (COMB) (p = 0.0056; corrected p = 0.0006). AVPR1A haplotype AVR+RS1 further suggested a positive association with ST (p = 0.0038; corrected p = 0.00184) and COMB (p = 0.0083; corrected p = 0.0040) using haplotype-based association test HBAT. The results suggest that the neurobiology of music perception and production is likely to be related to the pathways affecting intrinsic attachment behavior.