title: A re-review of the association between the NOTCH4 locus and schizophrenia.
abstract: NOTCH4 has long been identified as a candidate susceptibility gene for schizophrenia, but the collective body of genetic association studies of this gene has been less than conclusive. Recently a variant in NOTCH4 was implicated as one of the most reliably associated polymorphisms observed in a genome-wide association scan of the disorder, and the collective evidence for this polymorphism now surpasses criteria for genome-wide significance. To place these developments in context, we now summarize the initial work identifying NOTCH4 as a candidate gene for schizophrenia. The results of the genome-wide association studies that have confirmed this as a risk gene, and novel bioinformatics analyses that reveal potential functional profiles of the most likely risk-conferring polymorphisms. These analyses suggest that the NOTCH4 polymorphisms most strongly associated with schizophrenia exert their effects on susceptibility by altering the efficiency and/or alternative splicing of Notch4 transcripts. Further experimental evidence should be pursued to clarify the NOTCH4-regulated molecular and cellular phenotypes of relevance to the disorder, and the functional consequences of the implicated polymorphisms in the gene.
authors.affiliation: Psychiatric Genetic Epidemiology & Neurobiology Laboratory, Department of Psychiatry & Behavioral Sciences, Medical Genetics Research Center, SUNY Upstate Medical University, Syracuse, New York 13210, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Shayevitz
authors.forename: Ori S
authors.initials: OS
authors.lastname: Cohen
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Glatt
mesh_terms: D056726:Genetic Association Studies; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*
chemical_list: C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D051880:Receptors, Notch