A recent report linked the human NOTCH4 locus with susceptibility to schizophrenia. In the June issue of Nature Genetics, two reports cast doubt on the NOTCH4-schizophrenia association. Sklar et al. conducted a large-scale study involving 519 parent-offspring trios in three independent families (compared to 80 trios in the original linkage study; Nature Genetics 2001, 28:126-128). Extensive association analyses failed to confirm the previous linkage results. McGinnis et al. analysed (CTG)n and (TAA)n microsatellite alleles in 300 Scottish schizophrenics and also failed to detect association (Nature Genetics 2001, 28:128-129). Thus, two large-scale studies employing transmission equilibrium test (TDT) analysis and case-control samples, suggest that there is not a general association between NOTCH4 and schizophrenia.