The signal on chromosome 7p15.3 is within SP4 (Figure 2), and comes almost entirely from females (P=4.44E-05 vs. 0.148 in males). Sp4 is specific to neurons and expressed primarily early in development52–54, forms complexes with estrogen receptors that influence regulation of many genes55, and could play a role in the mediation of neuroprotective enzymes and in glutamate-induced neurotoxicity.56, 57 Zhou et al. have reported that reduced expression of Sp4 in mice leads to hippocampal vacuolization, age-dependent reduced expression of neurotrophin 3 and deficits in sensorimotor gating and contextual memory54, possibly mediated by defects in the development of dentate gyrus cells.58 There is also evidence for a possible association between bipolar disorder and SNPs in the promoter of ADRBK2 (beta adrenergic receptor kinase 2, previously GRK3) which disrupt an Sp1/Sp4 binding site.59 Thus there are several mechanisms by which SP4 could play a role in psychiatric disorders.
