Evidence also exists to support linkage on chromosome 13. Stine and colleagues (1997) reported modest evidence of linkage to chromosome 13q32 in the NIMH Genetics Initiative pedigrees, and further support for this finding was reported by Detera-Wadleigh et al. (1999) in the Neurogenetics sample. Liu et al. (1999) and Kelsoe et al. (2001) have also reported suggestive findings of linkage on chromosome 13q.
With regard to more recent findings, in a sample of 65 probands with bipolar I disorder and 237 relatives affected with a major mood disorder, Potash et al. (2003) examined four chromosomal regions thought to confer genetic susceptibility to both schizophrenia and bipolar disorder. Diagnoses were made according to the RDC, and subsets of families were created based upon the number of members with psychotic mood disorder. Markers were microsatellite tandem repeats, and nonparametric linkage analysis was performed by using GENE-HUNTER (Kong and Cox 1997). The 10 families with three or more members with psychotic mood disorders showed suggestive evidence of linkage to 13q31, with a suggestive LOD score of 2.52, while these regions showed little evidence of linkage when the sample was examined in its entirety. Additionally, Badner and Gershon (2002) conducted a meta-analysis of published whole-genome scans of bipolar disorder and schizophrenia. The results show significant linkage for both disorders in the 13q region. Badenhop et al. (2002) reported a suggestive two-point LOD score of 2.29 for marker D13S153 (on 13q14) under a recessive model with a broadly defined disease phenotype, and Liu et al. (2003) reported a suggestive multipoint ASP LOD score of 2.2 under an intermediate diagnostic model for the D13S779 marker on 13q32.
Several association studies also implicate 13q in bipolar disorder. In an association study, Hattori et al. (2003) examined the relationship between the G72/G30 gene locus on 13q33 and bipolar disorder in two series of pedigrees, one from the Clinical Neurogenetics pedigrees (Berrettini et al. 1991), and another from the NIMH Genetic Initiative. The investigators performed transmission/disequilibrium testing
(TDT) and haplotype analysis. A similar haplotype was overtransmit-ted in both samples, which suggests that a susceptibility variant for bipolar disorder exists in this region. Given that several other papers have reported similar findings (Chen et al. 2004; Schumacher et al. 2004), it has recently been proposed that the relationship between the G72/G30 complex and bipolar disorder be considered a conclusive finding (DePaulo 2004). Ranade et al. (2003) examined linkage and association between bipolar disorder and serotonin type 2A receptor gene polymorphisms in a sample of 93 patients from Pennsylvania clinics and their parents (either one or both). Comparing the bipolar patients to controls revealed an association with SNPs on exons 2 and 3, consistent with haplotype differences. Examining patients and their parents suggested significant linkage and association with 1354C/T and haplo-types containing this SNP. These linkage and association studies suggest potential susceptibility loci somewhere on 13q, possibly for both bipolar disorder and schizophrenia or psychosis.
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