Five NOTCH4 polymorphisms show weak evidence for association with schizophrenia: evidence from meta-analyses

NOTCH4 initially received consideration as a risk gene for schizophrenia based on its location within a region on chromosome 6p that had previously shown strong evidence for genetic linkage with the illness. The initial published test for allelic association found strong evidence for involvement of this gene in schizophrenia, but subsequent studies failed to confirm this finding. Presently, we have used meta-analysis to derive a best estimate of the nature and magnitude of the associations between schizophrenia and five polymorphisms in and around the NOTCH4 gene. No significant association was detected between schizophrenia and repeat length of alleles at the (TAA)n, (CTG)n, or (TTAT)n polymorphisms, or between the disease and specific risk alleles at these polymorphisms or at the SNP1 or SNP2 polymorphisms. Heterogeneity and stronger evidence of association with the putative risk alleles of the (TAA)n, (CTG)n, SNP1, and SNP2 polymorphisms was observed in family-based studies than in case-control studies, suggesting that these polymorphisms may reliably influence risk for schizophrenia under certain circumstances. Since more consistent and robust associations with schizophrenia risk have been observed for haplotypes of these polymorphisms [especially those containing SNP2 and (CTG)n], additional large family-based or genomic-controlled studies would be helpful for definitively specifying the role of NOTCH4 haplotypes in risk for schizophrenia.