Human Molecular Genetics Advance Access originally published online on August 2, 2007
Human Molecular Genetics 2007 16(20):2517-2528; 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 and 2 Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland, 3 Department of Psychology and 4 Department of Medical Genetics, University of Helsinki, Helsinki, Finland, 5 Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland and 6 The Broad Institute, MIT, Boston, MA, USA
* To whom correspondence should be addressed at: Department of Molecular Medicine, Biomedicum, National Public Health Institute, PO Box 104, Helsinki 00251, Finland. Tel: +358 947448751; Fax: +358 947448480; E-mail: tiina.paunio{at}ktl.fi
Received March 22, 2007; Accepted July 23, 2007
Bipolar disorder (BPD) and schizophrenia (SCZ) have at least a partially convergent aetiology and thus may share genetic susceptibility loci. Multiple lines of evidence emphasize the role of disrupted-in-schizophrenia-1 (DISC1) gene in psychotic disorders such as SCZ. We monitored the association of allelic variants of translin-associated factor X (TSNAX)/DISC1 gene cluster using 13 single-nucleotide polymorphisms (SNPs) in 723 members of 179 Finnish BPD families. Consistent with an earlier finding in Finnish SCZ 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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