2006; Joseph et al. 2008; Bora et al. 2009; Kurtz and Gerraty 2009) and, to a lesser extent, major depression (Snyder 2013). These endophenotypes may be

more closely related to genetic variation (Gottesman and Gould 2003) and provide a window into specific vulnerabilities that increase the probability of mood disorder evolution. A growing number of studies have evaluated the relationships between candidate genes and cognitive processes or brain volumes in healthy and mood disordered samples (Bigos et al. 2010; Krug et al. 2010; Thimm et al. 2011; Frodl et al. 2012; Radua et al. 2012). For example, Frodl et al. (2012) identified associations of genes important for glucocorticoid Inhibitors,research,lifescience,medical and immune function with hippocampal volume in patients with major depressive disorder. HSP inhibitor Previous data from our group has found altered anterior cingulate volumes Inhibitors,research,lifescience,medical in individuals with bipolar disorder who carried the BDNF minor allele (Matsuo et al. 2009). A single nucleotide polymorphism (SNP)

rs1006737 in CACNA1C, implicated in bipolar disorder (Ferreira et al. 2008) and other neuropsychiatric disorders (Gargus 2006, 2009), has been found to increase brain volumes, particularly grey matter volumes (Kempton et al. 2009), and impair appropriate functioning of fronto-temporal circuits (Wang et al. 2011) important for emotional processing (Radua et al. 2012). Inhibitors,research,lifescience,medical Similarly, variations in ANK3 and DGKH, also implicated in bipolar Inhibitors,research,lifescience,medical disorder (Baum et al. 2008) and other neuropsychiatric disorders (Weber et al. 2011), have been associated with altered brain structure and function (Hatzimanolis et al. 2012; Linke et al. 2012; Whalley et al. 2012). Taken together, these data support a model where genes important for ongoing neural plasticity and immune system functioning influence cognitive and structural brain endophenotypes representing key nodes of mood disorder vulnerability. The present study evaluated four strong candidate polymorphisms from genes important for neurotransmission and plasticity – ANK3 (rs10994336), BDNF (rs6265), CACNA1C (rs1006737), and Inhibitors,research,lifescience,medical DGKH (rs1170191). The functionality

of the intronic variants in ANK3, CACNA1C, and DGKH have not been demonstrated. However, it was reported that CACNA1C rs1006737 AA genotype subjects have greater mRNA expression in the dorsolateral prefrontal see more cortex than subjects with GG or GA genotypes (Bigos et al. 2010). Additionally, each of these candidate polymorphisms is believed to have functional relevance to neuropsychiatric disorders, including mood disorder: ANK3 is thought to influence the function of voltage-gated sodium channels, BDNF regulates neuronal growth and participates in plasticity of neurons throughout the lifespan, CACNA1C is the alpha 1C subunit of the L-type voltage-gated calcium channel, and DGKH participates in the lithium-sensitive phosphatidyl inositol pathway.