The biological functions of DISC1 fit well with current aetiological concepts in SZ-related major mental illness and cognition.28 DISC1 is a scaffold protein that interacts with, and modulates the activity of, multiple proteins with key roles in neurodevelopment, neurogenesis, neuronal migration, integration and signalling29, 30, 31 including the antidepressant and antipsychotic targets GSK3β32 and PDE4.33 Several common and rare amino-acid polymorphisms of DISC1 have predicted deleterious effects on protein function and demonstrable biological effects in experimental settings.31 The 704C allele is associated with reduced activity of ERK1 and Akt kinases, altered binding affinities of DISC1 for NDE1 and NDEL1 and variation in DISC1 oligomeric status.34, 35, 36, 37 The 607F allele results in (a) reduced binding and centrosomal localisation of PCM1, (b) reduced noradrenaline neurotransmitter release in SH-SY5Y cells,38 (c) altered mitochondrial trafficking39 and (d) a partial shift from neuronal to glial expression in the brain.40 Furthermore, Singh et al.41 reported that 607F impacts negatively on neural progenitor proliferation in E16 mouse brain, correlates with aberrant wnt signalling in human lymphoblasts, and is associated with a neurodevelopmental phenotype in morpholino
