Comprehensive genomic analyses associateUGT8variants with musical ability in a Mongolian population

Abstract

BackgroundMusical abilities such as recognising music and singing performance serve as means for communication and are instruments in sexual selection. Specific regions of the brain have been found to be activated by musical stimuli, but these have rarely been extended to the discovery of genes and molecules associated with musical ability.MethodsA total of 1008 individuals from 73 families were enrolled and a pitch-production accuracy test was applied to determine musical ability. To identify genetic loci and variants that contribute to musical ability, we conducted family-based linkage and association analyses, and incorporated the results with data from exome sequencing and array comparative genomic hybridisation analyses.ResultsWe found significant evidence of linkage at 4q23 with the nearest marker D4S2986 (LOD=3.1), whose supporting interval overlaps a previous study in Finnish families, and identified an intergenic single nucleotide polymorphism (SNP) (rs1251078, p=8.4×10−17) near UGT8, a gene highly expressed in the central nervous system and known to act in brain organisation. In addition, a non-synonymous SNP in UGT8 was revealed to be highly associated with musical ability (rs4148254, p=8.0×10−17), and a 6.2 kb copy number loss near UGT8 showed a plausible association with musical ability (p=2.9×10−6).ConclusionsThis study provides new insight into the genetics of musical ability, exemplifying a methodology to assign functional significance to synonymous and non-coding alleles by integrating multiple experimental methods.

Convergent evidence for the molecular basis of musical traits

“…2), the region showing strongest evidence for linkage and association with musical abilities3739. All these seven genes show major evidence from human studies, while receiving only supporting evidence from animal studies (Table 2).…”

“…Over the past decade, several studies ranging from candidate gene level to genome-wide scans have investigated the molecular basis of musical traits in humans. For example, conventional genetic approaches such as genome-wide linkage scans, association studies3678 and CNV studies910 have shown that musical aptitude is linked to regions that contain genes affecting development and function of auditory pathway and neurocognitive processes. Studies of genome-wide RNA expression profiles have revealed that listening and performing music enhanced the activity of genes related to dopamine secretion and transport, neuronal plasticity, learning and memory1112.…”

Defining the biological bases of individual differences in musicality

“…The AVPR1A gene is one well-studied example [58 -61]. However, recent genome-wide screens failed to find significant effects for any prior-studied candidates, including AVPR1A [62,63]. (d ) CNVs.…”

“…(e) Combined approach, using linkage, association, CNV analyses and sequencing. Park et al [63] studied pitchproduction accuracy in a multi-stage approach. They began with a linkage screen, identifying a broad linkage peak on chromosome 4q23, and followed up with association analyses of the surrounding region, eventually zooming in on the UGT8 gene in 4q26 as a candidate.…”

“…The largest genetic association studies of musical skills reported thus far (e.g. [62,63]; table 2) have involved sample sizes that are small when compared with GWAS studies in other complex genetic traits, and so have been relatively underpowered. Studies with low power may fail to detect effects that are biologically real and, at the same time, are more susceptible to false-positive results, in which spurious genotype -phenotype correlations are observed [86].…”