Human Molecular Genetics Advance Access originally published online on October 7, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 23 3151-3159
DOI: 10.1093/hmg/ddg341
© 2003 Oxford University Press
Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects
1Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland, 2Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland, 3Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland, 4Millennium Pharmaceuticals Inc, Cambridge, MA, USA, 5Department of Medical Genetics, University of Helsinki, Finland and 6The David Geffen School of Medicine at UCLA, California, USA
Received August 8, 2003; Accepted October 2, 2003
We have previously reported a linkage peak on 1q42 in a Finnish schizophrenia sample. In this study we genotyped 28 single nucleotide polymorphisms (SNPs) from 1q42 covering the three candidate genes TRAX, DISC1 and DISC2, using a study sample of 458 Finnish families ascertained for schizophrenia. Two-point and haplotype association analysis revealed a significant region of interest within the DISC1 gene. A common haplotype (HEP3) was observed to be significantly under-transmitted to affected individuals (P=0.0031). HEP3 represents a two SNP haplotype spanning from intron 1 to exon 2 of DISC1. This haplotype also displayed sex differences in transmission distortion, the under-transmission being significant only to affected females (P=0.00024). Three other regions of interest were observed in the TRAX and DISC genes. However, analysis of only those families with complete genotype information specifically highlights the HEP3 haplotype as a true observation. The finding of a common under-transmitted SNP haplotype might imply that this particular allele offers some protection from the development of schizophrenia. Analysis of component-traits of schizophrenia, derived from the Operational Criteria Checklist of Psychotic Illness (OCCPI), displayed association of HEP3 to features of the general phenotype of schizophrenia, including traits representing delusions, hallucinations and negative symptoms. This study provides further evidence for the hypothesis that the DISC1 gene is involved in the aetiology of schizophrenia, and implies a putative sex difference for the effect of the gene. Our findings would also encourage more detailed analyses of the effect of DISC1 on the component-traits of schizophrenia.
* To whom correspondence should be addressed at: Biomedicum/KTL, MLO, PL 104, 00251, Helsinki, Finland. Tel: +358 94744-8393; Fax: +358 947448480; Email: leena.peltonen{at}ktl.fi
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