| Summary: | An improved diagnostic and phenotyping instrument for synaesthesia (the Revised Test of Genuineness, TOG-R) was developed as the first phase of this project and used to diagnose and phenotype 43 families (n=196) with auditory-visual synaesthesia. Computer simulations confirmed that the sample had more than adequate power to detect a major gene effect. A whole-genome linkage scan using 410 microsatellite markers (mean inter-marker distance=9.05cM, mean information content=0.710) was performed. NPL analysis was conducted using MERLIN 1.1a/MINX 1.1a 14 potential candidate regions (LOD > 1) were fine-mapped at 5cM density and subjected to NPL analysis. An HLOD score analysis of the fine-mapping data for applicable chromosomes and the primary genome scan data for the remainder of the genome was also performed to address potential sample heterogeneity. Four candidate regions were identified, with the HLOD analysis detecting linkages missed out by the NPL analysis indicating substantial genetic heterogeneity. Significant linkage at the genome-wide level was detected to chromosome 2q (HLOD=3.025, empirical genome-wide <i>p</i>=0.047). Suggestive linkage (LOD > 2.2) was found to chromosomes 5q, 6p, and 12p. No support was found for linkage to the X-chromosome; furthermore, the study has identified the first confirmed cases of male-to-male transmission of synaesthesia. The results of this study that synaesthesia is a complex disorder with multiple modes of inheritance and substantial locus heterogeneity. Further work will include the development of endophenotypes and SNP-based fine-mapping or association studies.
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