Recently, several candidate susceptibility genes of small effects for schizophrenia have been replicated in association studies. However, their possible roles in the manifestation of the disease remain obscure (1). Therefore, we read with great interest the article by Ayman H. Fanous, M.D., and colleagues (2), which described the relationship between a high-risk haplotype in the DTNBP1 gene and clinical features of schizophrenia. The conclusion—that the etiologically relevant variation in DTNBP1 in presumptive linkage disequilibrium with the high-risk haplotype might be associated with high levels of negative symptoms—was derived from the observation that the high-risk haplotype frequency was higher in the subjects in the upper 40th percentile for the negative symptom factor.
However, the data in their Table 2 might suggest the opposite possibility. First, the frequency of the high-risk haplotype was higher in the upper 20%–40% subgroup for the negative symptom factor than in the upper 0%–20% subgroup (0.098 and 0.075, respectively). In addition, the high-risk haplotype frequencies in the upper 40% subgroup for four factors (negative, hallucinations, delusions, and manic) were higher in the broad-definition group than in the narrow-definition group. These results suggest that the high-risk haplotype in DTNBP1 was overtransmitted to the milder cases with schizophrenia, which is just the opposite of their interpretation.
This might be the same with NRG1, another best-replicated positional candidate gene for schizophrenia. The high-risk haplotypes were associated with nondeficit schizophrenia but not with deficit schizophrenia (3).
A significant p value in an association study tells us nothing about the nature of the causal relationship between the gene and the disease (1). Therefore, it should be noted that a significant positive association with a disease does not necessarily imply susceptibility but rather may indicate resistance to the disease.
According to Kendler (4), one of the most perplexing problems concerned with the schizophrenia-DTNBP1 connection is that although reduced levels of DTNBP1 were seen in the hippocampus of nearly all affected cases, only a subset of individuals with schizophrenia carries the high-risk DTNBP1 haplotypes that reduce DTNBP1 expression in the brain (5). However, if the high-risk haplotypes in DTNBP1 were resistance genes and a reduced DTNBP1 level in the brain was a resistance response to the pathogenesis of the disease, the brains of most patients would show such a change and a subset of patients who carry apparent high-risk DTNBP1 haplotypes should have a genetically determined resistance that makes the disease milder.
Kendler KS: “A gene for…”: the nature of gene action in psychiatric disorders. Am J Psychiatry 2005; 162:1243–12522.
Fanous AH, van den Oord EJ, Riley BP, Aggen SH, Neale MC, O’Neill FA, Walsh D, Kendler KS: Relationship between a high-risk haplotype in the DTNBP1 (dysbindin) gene and clinical features of schizophrenia. Am J Psychiatry 2005; 162:1824–1832
Bakker SC, Hoogendoorn MLC, Selten J-P, Verduijn W, Pearson PL, Sinke RJ, Kahn RS: Neuregulin 1: genetic support for schizophrenia subtypes. Mol Psychiatry 2004; 9:1061–10634.
Kendler KS: Schizophrenia genetics and dysbindin: a corner turned? (editorial). Am J Psychiatry 2004; 161:1533–15365.
Bray NJ, Preece A, Williams NM, Moskvina V, Buckland PR, Owen MJ, O’Donovan MC: Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression. Hum Mol Genetics 2005; 14:1947–1954