30 †Joint supervision 31 32 2 33Abstract 34
35While timing and rhythm-related phenotypes are heritable, the human genome 36 variations underlying these traits are not yet well-understood. We conducted a genome-37 wide association study to identify common genetic variants associated with a self-38 reported musical rhythm phenotype in 606,825 individuals. Rhythm exhibited a highly 39 polygenic architecture with sixty-eight loci reaching genome-wide significance 40 (p<5x10 -8 ) and SNP-based heritability of 13%-16%. Polygenic scores for rhythm 41 predicted the presence of musician-related keywords in the BioVU electronic health 42 record biobank. Genetic associations with rhythm were enriched for genes expressed in 43 brain tissues. Genetic correlation analyses revealed shared genetic architecture with 44 several traits relevant to cognition, emotion, health, and circadian rhythms, paving the 45 way to a better understanding of the neurobiological pathways of musicality. 46 47 48 49 50We conducted a genome-wide association study (GWAS) to identify common 73 genetic variants associated with a self-reported musical rhythm phenotype, i.e. "Can 74 you clap in time with a musical beat?", collected from 606,825 individuals participating in 75 research with the personal genetics company 23andMe, Inc. We then validated this self-76 reported phenotype in a separate internet-based behavioural study conducted in 724 77 individuals and found that it was significantly correlated with rhythm perception (Online 78 Methods). In the GWAS, a total of 68 independent SNPs surpassed the threshold for 79 genome-wide significance (p<5x10 -08 ). In addition to determining which genes were 80 implicated by these variants, we estimated how much of the total phenotypic variance 81 could be explained by all variation across the genome (i.e., SNP-based heritability). We 82 then further explored this heritability to test the hypothesis that variants associated with 83 rhythm were enriched among genes expressed in brain compared to genes expressed 84 in other tissues (e.g., muscle, adipose, etc.), and furthermore enriched in genes 85 expressed in neurons compared to other brain cell types (e.g., oligodendrocyte, 86 astrocyte). 87Using an independent sample of 67,441 genotyped individuals from the 88 Vanderbilt University Medical Center biobank, BioVU, we tested whether a cumulative 89 sum of the genetic effects for rhythm detected in our GWAS (i.e., rhythm polygenic 90 score), was significantly associated with an indication of musician status in the 91 electronic health record (EHR). Because little is yet known about the relationship of the 92 genomics of rhythm to other traits, we also performed exploratory genetic correlation 93 analysis including 764 complex traits for which a well-powered GWAS has been 94 performed and deposited in LDHub 16 . Finally, we evaluated the contribution to rhythm 95 deviation increase in the rhythm discrimination test). In the remainder of the paper, the 122 "rhythm" trait in our study refers to the self-reported b...