Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects.
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.
Hennah
William
W
Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland.
Varilo
Teppo
T
Kestilä
Marjo
M
Paunio
Tiina
T
Arajärvi
Ritva
R
Haukka
Jari
J
Parker
Alex
A
Martin
Rory
R
Levitzky
Steve
S
Partonen
Timo
T
Meyer
Joanne
J
Lönnqvist
Jouko
J
Peltonen
Leena
L
Ekelund
Jesper
J
D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D012559:Schizophrenia / Q000235:genetics*; D012737:Sex Factors
C412476:DISC1 protein, human; C448722:DISC2 gene product, human; D009419:Nerve Tissue Proteins; D062085:RNA, Long Noncoding; D012333:RNA, Messenger