Human Molecular Genetics Advance Access published online on August 2, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm207
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Association of distinct allelic haplotypes of DISC1 with psychotic and bipolar spectrum disorders and with underlying cognitive impairments
1 Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland 2 Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland 3 Department of Psychology, University of Helsinki, Helsinki, Finland 4 Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland 5 Department of Medical Genetics, University of Helsinki, Helsinki, Finland 6 The Broad Institute, MIT, Boston, MA, USA
* Corresponding author: Tiina Paunio, National Public Health Institute, Department of Molecular Medicine, Biomedicum, P.O. Box 104, 00251 Helsinki, Finland. Tel: +358-9-47448751, Fax: +358-9-47448480, E-mail: Tiina.Paunio{at}ktl.fi
Received March 22, 2007; Revised July 23, 2007; Accepted July 23, 2007
Bipolar disorder (BPD) and schizophrenia have at least a partially convergent aetiology and thus may share genetic susceptibility loci. Multiple lines of evidence emphasize the role of DISC1 (Disrupted-in-Schizophrenia-1) gene in psychotic disorders such as schizophrenia. We monitored for association of allelic variants of TSNAX/DISC1 gene cluster using 13 SNPs in 723 members of 179 Finnish BPD families. Consistent with an earlier finding in Finnish schizophrenia families, the haplotype T-A of rs751229 and rs3738401 at the 5' end of DISC1 was over-transmitted to males with psychotic disorder (p=0.008; for an extended haplotype p=0.0007 with both genders). Haplotypes at the 3' end of DISC1 associated with bipolar spectrum disorder (p=0.0002 for an under-transmitted haplotype T-T of rs821616 and rs1411771, for an extended haplotype p=0.0001), as did a two-SNP risk haplotype at the 5'end of TSNAX (p=0.007). The risk haplotype for psychotic disorder also associated to perseverations (p=0.035; for rs751229 alone p=0.0012), and a protective haplotype G-T-G with rs1655285 in addition to auditory attention (p=0.0059). The 3'end variants associated with several cognitive traits, with the most robust signal for rs821616 and verbal fluency and rs980989 and psychomotor processing speed (p=0.011 for both). These results support involvement of DISC1 in the genetic aetiology of BPD and suggest that its distinct variants contribute to variation in the dimensional features of psychotic and bipolar spectrum disorders. Finding of alternative associating haplotypes in the same set of BPD families gives evidence for allelic heterogeneity within DISC1, eventually leading to heterogeneity in the clinical outcome as well.
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