Absolute pitch (AP) is the ability to recognize a pitch, without an external reference. By surveying more than 600 musicians in music conservatories, training programs, and orchestras, we have attempted to dissect the influences of early musical training and genetics on the development of this ability. Early musical training appears to be necessary but not sufficient for the development of AP. Forty percent of musicians who had begun training at <=4 years of age reported AP, whereas only 3% of those who had initiated training at >=9 years of age did so. Self-reported AP possessors were four times more likely to report another AP possessor in their families than were non-AP possessors. These data suggest that both early musical training and genetic predisposition are needed for the development of AP. We developed a simple computer-based acoustical test that has allowed us to subdivide AP possessors into distinct groups, on the basis of their performance. Investigation of individuals who performed extremely well on this test has already led us to identify several families that will be suitable for studies of the genetic basis of AP.

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Manic depressive illness, or bipolar disorder (BP), is characterized by episodes of elevated mood (mania) and depression. We designed a multistage study in the genetically isolated population of the Central Valley of Costa Rica to identify genes that promote susceptibility to severe BP (termed BPI), and screened the genome ot two Costa Rican BPI pedigrees (McInnes et al., submitted). We considered only individuals who fulfilled very stringent diagnostic criteria for BPI to be affected. The strongest evidence for a BPI locus was observed in 18q22-q23. We tested 16 additional markers in this region and seven yielded peak lod scores over 1.0. These suggestive lod scores were obtained over a far greater chromosomal length (about 40 cM) than in any other genome region. This localization is supported by marker haplotypes shared by 23 of 26 BPI affected individuals studied. Additionally, marker allele frequencies over portions of this region are significantly different in the patient sample from those of the general Costa Rican population. Finally, we performed an analysis which made use of both the evidence for linkage and for association in 18q23, and we observed significant lod scores for two markers in this region.

Bipolar mood disorder (BP) is a debilitating syndrome characterized by episodes of mania and depression. We designed a multistage study to detect all major loci predisposing to severe BP (termed BP-I) in two pedigrees drawn from the Central Valley of Costa Rica, where the population is largely descended from a few founders in the 16th-18th centuries. We considered only individuals with BP-I as affected and screened the genome for linkage with 473 microsatellite markers. We used a model for linkage analysis that incorporated a high phenocopy rate and a conservative estimate of penetrance. Our goal in this study was not to establish definitive linkage but rather to detect all regions possibly harboring major genes for BP-I in these pedigrees. To facilitate this aim, we evaluated the degree to which markers that were informative in our data set provided coverage of each genome region; we estimate that at least 94% of the genome has been covered, at a predesignated threshold determined through prior linkage simulation analyses. We report here the results of our genome screen for BP-I loci and indicate several regions that merit further study, including segments in 18q, 18p, and 11p, in which suggestive lod scores were observed for two or more contiguous markers. Isolated lod scores that exceeded our thresholds in one or both families also occurred on chromosomes 1, 2, 3, 4, 5, 7, 13, 15, 16, and 17. Interesting regions highlighted in this genome screen will be followed up using linkage disequilibrium (LD) methods.

Absolute pitch (AP) is a behavioral trait that is defined as the ability to identify the pitch of tones in the absence of a reference pitch. AP is an ideal phenotype for investigation of gene and environment interactions in the development of complex human behaviors. Individuals who score exceptionally well on formalized auditory tests of pitch perception are designated as "AP-1." As described in this report, auditory testing of siblings of AP-1 probands and of a control sample indicates that AP-1 aggregates in families. The implications of this finding for the mapping of loci for AP-1 predisposition are discussed.