Positional Pathway Screen of wnt Signaling Genes in Schizophrenia: Association with DKK4

Background: Wnt signaling has been implicated in schizophrenia from studies of gene expression in patients, from an understanding of the function of reported susceptibility genes and from experimental studies of psychoactive drugs. This diverse evidence suggests that wnt signaling genes, defined as pathway participants, modifiers or targets, are good candidates as susceptibility factors. Methods: We performed a combined positional and candidate association screen by identifying known wnt signaling genes in regions linked to schizophrenia. In a staged study we examined over 50 single nucleotide polymorphisms (SNPs) in 28 wnt signaling genes, first in trios of Chinese origin and then in a case-control series from Hong Kong. Results: In both sets, Dickkopf 4 (DKK4) was associated with schizophrenia – with an odds ratio of 3.9 (p <.01, CI = 1.3-11.1) in the combined sample. Conclusions: As DKK family members have previously been found to show altered expression in schizophrenia brain and to bind to neuregulin, this finding suggests that DKK4 may play a role in schizophrenia pathogenesis.