Association of the HOPA12bp allele with a large X-chromosome haplotype and positive symptom schizophrenia
Article first published online: 11 FEB 2004
Copyright © 2004 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 127B, Issue 1, pages 20–27, 15 May 2004
How to Cite
Spinks, R., Sandhu, H. K., Andreasen, N. C. and Philibert, R. A. (2004), Association of the HOPA12bp allele with a large X-chromosome haplotype and positive symptom schizophrenia. Am. J. Med. Genet., 127B: 20–27. doi: 10.1002/ajmg.b.20175
- Issue published online: 20 APR 2004
- Article first published online: 11 FEB 2004
- Manuscript Accepted: 20 OCT 2003
- Manuscript Received: 27 JUN 2003
- Nellie Ball Trust for Schizophrenia Research
- NIMH. Grant Number: K08MH064714
- NIMH. Grant Numbers: MH31593, MH43271, MH40856, MH60990
- nuclear receptor co-activator;
HOPA is a X-chromosome gene that encodes an essential nuclear receptor co-activator. Previously, we have demonstrated that an exonic polymorphism, termed HOPA12bp, in the Opa (Opposite Paired) domain of this gene that is critical for neuronal growth and differentiation is associated with a low risk for schizophrenia. But curiously, we have also noted that all HOPA12bp probands have the same haplotype immediately surrounding the HOPA12bp, and other investigators have found evidence of population stratification with the HOPA12bp allele. Since deleterious alleles are weeded from the population, and the HOPA12bp allele is not rare, these prior findings suggest the possibility that positive selection may be occurring with respect to the HOPA12bp allele and that unique phenotypic features may be associated with this allele. To test these hypotheses, we analyzed symptom data collected from schizophrenic probands and conducted haplotyping studies around the HOPA12bp polymorphism. Consistent with our hypotheses, genotyping studies of 43 unrelated HOPA12bp males and 137 HOPAwild males demonstrated that the HOPA12bp allele is associated with a large conserved DNA haplotype that extends over several genes known to be critical for human survival. Furthermore, ANOVA analysis of symptom data demonstrated that HOPA12bp schizophrenic probands (n = 14) have significantly lower severity of negative symptoms (P < 0.002) and better attention (P < 0.002) than matched controls (n = 30). Taken together, these findings further refine the behavioral endophenotype associated with the HOPA12bp allele and suggest that the sequence surrounding HOPA may need to be considered to fully understand the molecular basis of the phenotype associated with the HOPA12bp allele. © 2004 Wiley-Liss, Inc.