Our study offers several advantages for studying genetic associations with physiological parameters and might be generalizable to other genotype-phenotype studies based on different types of time series (e.g., brain electroactivity or time series derived from functional magnetic resonance imaging). First, our method enables us to cluster heart rate dynamics by an IBS method based on their acceleration/deceleration patterns of heartbeat sequence. The IBS method was not exclusively developed for the analysis of heartbeat sequence but also for other generic datasets consisting of repetitive elements [42, 43] . With an appropriate mapping rule that is meaningful to a target dataset, the IBS method can be applied to other types of phenotypic data derived from the time series [16] . Second, we employed a visually aided hierarchical analysis by a software tool called a generalized association map, which enables a bottom-up approach to unsupervisedly identify heart rate clusters to study genotype-phenotype associations. This bottom-up approach may help reduce the false-positivity commonly seen in conventional association studies. b 1 -AR is the predominant b-AR subtype in the heart. Compared to activation of b 2 -AR, stimulation in b 1 -AR can result in more Figure 2 . Unsupervised, hierarchical cluster tree of subjects according to the pairwise dissimilarity matrix among heart rate dynamics using an information-based similarity index method. Dissimilarity matrix data were visualized and clustered by a generalized association plot algorithm [58] . The bars on the left indicate the b-adrenergic receptor (b-AR) gene polymorphisms rs1801252 (green: homozygous Ser49 carriers; blue: Gly16 allele carriers; red: unknown genotype), rs1042713 (green: homozygous Arg16 carriers; blue: Gly16 allele carriers) and rs1042714 (green: homozygous Gln27 carriers; blue: Glu27 allele carriers). doi:10.1371/journal.pone.0019232.g002 significantly increased frequency and contractility of heart. Although substantial efforts have been made to link b 1 -AR polymorphisms with cardiovascular function, studies have been mixed in this regard. For example, b 1 -AR Ser49Gly polymorphism was found to be associated with increased blood pressure and heart rate [14, 15] but data are inconsistent in our findings and other reports [48, 49] . Because we studied only one polymorphism in b 1 -AR, further research is needed to identify other possible b 1 -AR polymorphisms associated with HRV.