الفهرس 
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Abstract
Though circadian function can be disrupted in BD1, the relationship between circadian function and liability to BD1 has not been investigated systematically. The present study was conducted on 146 patients (probands) fulfilled DSM IV criteria for Bipolar I Disorder in the Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania State, United States. Available parents of those probands (n = 197) were included in the present study and served as familybased controls in the linkage analysis. Since disruption in circadian function have been reported among patients with unipolar depression (UPD), as well as schizophrenia (SZ) (Healy and Waterhouse 1995) (Rao, Strebel et al. 1995), and familial aggregation of BD1, UPD and SZ is well known, raising the possibility that etiological factors and pathogenic mechanisms may be shared. Therefore, we investigated patients with schizophrenia / schizoaffective disorder (n = 334) and their parents (n = 329) as an additional comparison group in the present studies. We also analyzed a smaller BD1 caseparent sample recruited by the NIMH (n = 96 trios). Our Results illustrated the followings: ??Multivariate analyses revealed significant groupwise differences between the BD1 cases and the comparison groups. Overall, BD1 cases had higher ?eveningness? scores than controls, suggesting phase related difference in circadian function. ??Exploratory analyses revealed that earlier age at onset and likelihood of rapid mood swings were separately associated with ?eveningness? among the BD1, but not the SZ/SA patients. ??Significant correlations between circadian gene SNPs and M/E scores were not observed among the parents or the BD1 patients. ??However, analysis of smaller samples using the Quantitative transmission disequlibrium test (QTDT) revealed suggestive associations at BmaL I among BD1, as well as SZ/SA patients and with the TIMELESS gene among the BD1 patients. ??Using the transmission disequilibrium test (TDT) and casecontrol comparisons, modest associations between BD1 liability and SNPs at Bmal I, TIMELESS and PERIOD 3 genes were observed. ??Significant associations were detected between BD1 and three SNPs at the Bmal1 locus and one SNP each at the PER3 and TIMELESs loci. Associations with related haplotypes were also present, the most consistent results being at Bmal1. ??To investigate whether the associations were limited to BD1, we also evaluated the associated SNPs among 340 cases with schizophrenia or schizoaffective disorder (SZ/SZA) and their parents. Associations with SNPs at Bmal1, Per3 and Tim were present in this group also, but the associated SNPs and the magnitude of the associations differed from the BD1 sample. ??However, the associations were not detected in a smaller BD1 sample recruited by the NIMH Collaborative Genetics Initiative (n = 96 caseparent trios). Our results were discussed in light of the previous literatures.? In conclusion, the present study demonstrated the following: ??BD1 patients differ from controls with respect to phasic differences in M/E, estimated through CS scores. ??Though variation in circadian genes is not clearly associated with CS scores among such patients, genetic associations with BD1 liability are more likely. Thus, circadian variation may be intimately related to the genesis of BD1. ??Similar changes are also observed among SZ/SA cases, but the pattern and magnitude of the changes is distinct from BD1.