Converging evidence that sequence variations in the novel candidate gene MAP2K7 (MKK7) are functionally associated with schizophrenia

Abstract

Schizophrenia is a debilitating psychiatric disease with a strong genetic contribution, potentially linked to altered glutamatergic function in brain regions such as the prefrontal cortex (PFC). Here, we report converging evidence to support a functional candidate gene for schizophrenia. In post-mortem PFC from patients with schizophrenia, we detected decreased expression of MKK7/MAP2K7-a kinase activated by glutamatergic activity. While mice lacking one copy of the Map2k7 gene were overtly normal in a variety of behavioural tests, these mice showed a schizophrenia-like cognitive phenotype of impaired working memory. Additional support for MAP2K7 as a candidate gene came from a genetic association study. A substantial effect size (odds ratios: ~1.9) was observed for a common variant in a cohort of case and control samples collected in the Glasgow area and also in a replication cohort of samples of Northern European descent (most significant P-value: 3 × 10(-4)). While some caution is warranted until these association data are further replicated, these results are the first to implicate the candidate gene MAP2K7 in genetic risk for schizophrenia. Complete sequencing of all MAP2K7 exons did not reveal any non-synonymous mutations. However, the MAP2K7 haplotype appeared to have functional effects, in that it influenced the level of expression of MAP2K7 mRNA in human PFC. Taken together, the results imply that reduced function of the MAP2K7-c-Jun N-terminal kinase (JNK) signalling cascade may underlie some of the neurochemical changes and core symptoms in schizophrenia.

JNK1 controls dendritic field size in L2/3 and L5 of the motor cortex, constrains soma size, and influences fine motor coordination

“…Genetic anomalies at several levels of the JNK cascade confer susceptibility to psychiatric disorders (Weiss et al, 2008; de Anda et al, 2012; Winchester et al, 2012; Kunde et al, 2013; Coffey, 2014), indicating that disturbance of the JNK pathway may be central to the pathology. Among these, schizophrenia and autism stand out as dendrite disorders that are accompanied by motor deficits.…”

“…For example, JNK1 activity in the cortex is dependent on a kinase located on chromosome 16p11.2, a gene susceptibility locus for autism and schizophrenia (Weiss et al, 2008; McCarthy et al, 2009). Genetic risk for schizophrenia is associated with the JNK pathway (Winchester et al, 2012), and the interleukin-1 receptor accessory protein like-1 gene, implicated in monogenic forms of mental retardation and autism, signals through JNK (Pavlowsky et al, 2010). Furthermore, chromosomal translocations leading to loss of function truncations of JNK3 are associated with intellectual disability (Shoichet et al, 2006; Baptista et al, 2008; Kunde et al, 2013).…”

Fine Mapping on Chromosome 13q32–34 and Brain Expression Analysis Implicates MYO16 in Schizophrenia

“…Given a potential convergence of MAP3K13 and PI3K pathways (Ambacher et al, 2012), regulation in trans of MAP3K13 may be mediated by altered MYO16 activity. Interestingly, MAP3K13 can phosphorylate MAP2K7 (mitogen-activated kinase protein 7), which has been recently implicated in schizophrenia (Winchester et al, 2012). In addition, the seven top-associated SNPs identified by our meta-analysis of the SAF2-GAIN-MGS data sets (Table 4) ), a gene implicated in brain maturation (Lindquist et al, 2011).…”

Mice haploinsufficient for Map2k7, a gene involved in neurodevelopment and risk for schizophrenia, show impaired attention, a vigilance decrement deficit and unstable cognitive processing in an attentional task: impact of minocycline

“…In this pathway, three genes ( MAPK8–10 ) encode isoforms of JNK (JNK1–3), which can be activated by either of the upstream kinases MKK4 or MKK7 (Wang et al 2007; Coffey 2014). Mutations in JNK3 cause severe intellectual disability (Shoichet et al 2006; Kunde et al 2013), whilst sequence variations in the MAP2K7 gene (encoding MKK7) are associated with prefrontal cortex dysfunction and cognitive impairment in schizophrenia (Winchester et al 2012). This is consistent with experimental evidence that JNK1, MKK7 and MAP3K12 (a kinase upstream of MKK7) are all crucial for the development of the neocortex (Hirai et al 2002; Hirai et al 2011; Yamasaki et al 2011; Riches and Reynolds 2014; Xu et al 2014), that JNK1 (Li et al 2007) and JNK2 (Chen et al 2005) mediate aspects of synaptic plasticity in the mature mouse hippocampus and that MKK7 orthologue mutation impairs long-term memory in Caenorhabditis elegans (Lakhina et al 2015).…”

“…Several neurochemical and metabolic changes observed in patients are centred on the prefrontal cortex, a region involved in multiple cognitive processes (Goldman-Rakic et al 2000), including a crucial role in aspects of normal attentional function (Rossi et al 2009). This raises the possibility that the decreased MKK7 expression, as observed in patients with schizophrenia (Winchester et al 2012), contributes directly to cognitive impairment.…”