Famine and
viral infection, as well as
interferon therapy have been reported to increase the risk of developing
bipolar disorder. In addition, almost 100 polymorphic genes have been associated with this disease. Several form most of the components of a
phosphatidyl-inositol signalling/AKT1 survival pathway (PIK3C3, PIP5K2A, PLCG1, SYNJ1, IMPA2, AKT1, GSK3B, TCF4) which is activated by
growth factors (
BDNF, NRG1) and also by
NMDA receptors (GRIN1, GRIN2A, GRIN2B). Various other
protein products of genes associated with
bipolar disorder either bind to or are affected by
phosphatidyl-inositol phosphate products of this pathway (ADBRK2, HIP1R, KCNQ2, RGS4, WFS1), are associated with its constituent elements (BCR, DUSP6, FAT, GNAZ) or are downstream targets of this signalling cascade (DPYSL2, DRD3, GAD1, G6PD, GCH1, KCNQ2, NOS3, SLC6A3, SLC6A4, SST, TH, TIMELESS). A further pathway relates to endoplasmic reticulum-stress (HSPA5, XBP1), caused by problems in protein glycosylation (ALG9),
growth factor receptor sorting (PIK3C3, HIP1R, SYBL1), or aberrant
calcium homoeostasis (WFS1). Key processes relating to these pathways appear to be under circadian control (ARNTL, CLOCK, PER3, TIMELESS). DISC1 can also be linked to many of these pathways. The
growth factor pathway promotes
protein synthesis, while the endoplasmic reticulum stress pathway, and other stress pathways activated by viruses and
cytokines (IL1B, TNF,
Interferons), oxidative stress or
starvation, all factors associated with
bipolar disorder risk, shuts down
protein synthesis via control of the
EIF2 alpha and beta translation initiation complex. For unknown reasons, oligodendrocytes appear to be particularly prone to defects in the translation initiation complex (
EIF2B) and the convergence of these environmental and genomic signalling pathways on this area might well explain their vulnerability in
bipolar disorder.