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.

Regulation of striatal dopamine responsiveness by Notch/RBP-J signaling

“…54 In addition to multiple lines of biological support on the implication of Notch in higher brain functions, psychiatric genetics have provided promising, but still slightly conflicting, evidence that suggests a set of genes in Notch signaling to be involved in psychiatric conditions, such as schizophrenia (also see Supplementary Figures 3a–d). 3, 4, 5, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 Together, the present study on Notch/RBP-J may provide novel insight not only in basic molecular signaling in the striatum but also in neurobiology of psychiatric conditions.…”

“…3, 4, 5 However, it remains unknown whether deficits in Notch/RBP-J signaling are involved in schizophrenia-like behavioral abnormalities or not. Notch/RBP-J signaling is highly conserved and known to play pivotal roles in various aspects of developmental neural cell fate specification, 6, 7, 8, 9, 10 dendrite morphogenesis 11, 12, 13 and neuronal functions in the adult central nervous system.…”

Reduced cortical thickness related to single nucleotide polymorphisms in the major histocompatibility complex region in antipsychotic‐naive schizophrenia

“…For example, rs3131296 is located in the largest intron (intron 18) of the neurogenic locus notch homolog protein 4 ( NOTCH4 ), which is one of the top candidate genes for schizophrenia (Allen et al, ). This SNP can affect the efficiency and/or alternative splicing of transcripts of NOTCH1 and NOTCH2 (Shayevitz, Cohen, Stephen, & Glatt, ; Thomas, Sikich, Lieberman, & LaMantia, ), and the NOTCH1 and NOTCH2 signaling pathways are known to be associated with cortical neurite growth via their roles in mediating the numbers of interneuronal contacts (Sestan, Tsakonas, & Rakic, ). Another SNP, rs1635, is located in exon 1 of NFKB ‐activating protein‐like ( NKAPL ) and encodes a threonine‐to‐glutamine substitution; this mutation may cause abnormal functioning of the NKAPL protein (Wu et al, ).…”

DNA methylation profiling in the thalamus and hippocampus of postnatal malnourished mice, including effects related to long-term potentiation

“…Moreover, approximately 60% of mammalian genes have CGI promoters, and methylated CGIs play an important role in gene silencing during processing [49]. The best-known producer of epigenesis, DNA methylation, plays an important role in regulating gene expression to preserve local activity states [50]. Epigenesis is defined as heritable changes in gene expression that are not accompanied by changes in DNA sequence [51].…”