1. ¹Medical Genetics Section, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Edinburgh, UK
2. ²MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK
3. ³Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK
4. ⁴Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK

Correspondence: Ms A Christoforou, Medical Genetics Section, Molecular Medicine Centre, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK. E-mail: A.Christoforou@ed.ac.uk

⁵These authors contributed equally to this work.

Received 22 August 2005; Revised 3 October 2005; Accepted 16 November 2005; Published online 3 January 2006.

Abstract

The orphan G protein-coupled receptor 78 (GPR78) gene lies within a region of chromosome 4p where we have previously shown linkage to bipolar affective disorder (BPAD) in a large Scottish family. GPR78 was screened for single-nucleotide polymorphisms (SNPs) and a linkage disequilibrium map was constructed. Six tagging SNPs were selected and tested for association on a sample of 377 BPAD, 392 schizophrenia (SCZ) and 470 control individuals. Using standard ² statistics and a backwards logistic regression approach to adjust for the effect of sex, SNP rs1282, located approximately 3 kb upstream of the coding region, was identified as a potentially important variant in SCZ (² P=0.044; LRT P=0.065). When the analysis was restricted to females, the strength of association increased to an uncorrected allele P-value of 0.015 (odds ratios (OR)=1.688, 95% confidence intervals (CI): 1.104–2.581) and uncorrected genotype P-value of 0.015 (OR=5.991, 95% CI: 1.545–23.232). Under the recessive model, the genotype P-value improved further to 0.005 (OR=5.618, 95% CI: 1.460–21.617) and remained significant after correcting for multiple testing (P=0.017). No single-marker association was detected in the SCZ males, in the BPAD individuals or with any other SNP. Haplotype analysis of the case–control samples revealed several global and individual haplotypes, with P-values <0.05, all but one of which contained SNP rs1282. After correcting for multiple testing, two haplotypes remained significant in both the female BPAD individuals (P=0.038 and 0.032) and in the full sample of affected female individuals (P=0.044 and 0.033). Our results provide preliminary evidence for the involvement of GPR78 in susceptibility to BPAD and SCZ in the Scottish population.