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Schizophrenia Schizophrenia is a highly heritable, genetically complex, and heterogeneous psychiatric syndrome. Twin and family studies estimate 80–85% of variance in disease liability can be accounted for by genetic factors (Cannon, Kaprio, Lonnqvist, Huttunen, & Koskenvuo, 1998). Thus, substantial efforts have been dedicated towards uncovering genetic loci increasing risk for schizophrenia. Though many methodologies have been employed including genome-wide surveys of common genetic polymorphisms (Purcell et al., 2009; Ripke et al., 2013; Schizophrenia Working Group of the Psychiatric Genomics, 2014), exome sequencing investigating rare variants (Fromer et al., 2014; Purcell et al., 2014), gene expression analyses (Gardiner et al., 2013; Guillozet-Bongaarts et al., 2014; Gulsuner et al., 2013), and integration of multiple methods (Hertzberg, Katsel, Roussos, Haroutunian, & Domany, 2015; Luo et al., 2015; van Eijk et al., 2014), nearly all gene-finding efforts in schizophrenia to date have employed diagnostic level classification as the phenotype of interest. However, there is substantial evidence that risk-increasing genes confer risk via impacting intermediate levels of impairment, such as cognitive dysfunction, suggesting that these may also be useful phenotypic targets in gene discovery studies (Cannon & Keller, 2006; Greenwood, Light, Swerdlow, Radant, & Braff, 2012; Lencz et al., 2014; Tan, Callicott, & Weinberger, 2008; Toulopoulou et al., 2007). Compared to the diagnosis of schizophrenia, which could imply dysfunction across a host of brain systems and signaling pathways, a given endophenotype provides a more constrained framework within which to interpret the functional-biological relevance of statistically identified genes (Heck et al., 2014; Ibrahim-Verbaas et al., 2015; Lencz et al., 2014). One of the most reliable endophenotypes in schizophrenia – and most profound areas of cognitive impairment – is verbal memory (Cannon et al., 2000; Greenwood et al., 2013; Schaefer, Giangrande, Weinberger, & Dickinson, 2013; van Erp et al., 2008). The California Verbal Learning Test (CVLT), a list-learning exercise, is a robust measure of memory impairment in schizophrenia (Haut, in prep; Stone et al., 2011; van Erp et al., 2008), is heritable (Carmelli, Swan, DeCarli, & Reed, 2002; Greenwood et al., 2007; Kremen et al., 2014; Panizzon et al., 2011), and shows intermediate levels of affection among relatives of patients with schizophrenia in twin and family studies (Greenwood et al., 2013; van Erp et al., 2008), supporting its role as a candidate endophenotype in genetic studies. Initial molecular genetic investigations of endophenotypes for schizophrenia have provided evidence that genes associated with putative cognitive endophenotypes at least partially overlap with those associated with schizophrenia (Heck et al., 2014; Lencz et al., 2014). However, so far this approach has been used largely to demonstrate the broad, shared genetic etiology between these phenotypes, rather than to identify specific genetic loci impinging on both, which is critical for elucidating the functional-physiologic significance of the underlying genetic associations. Furthermore, all of these studies have assayed common polymorphisms. Over 90% of common polymorphisms previously related to psychiatric illness are located in regulatory regions of DNA, rather than in coding regions where mutations more directly affect protein structure, suggesting that many of these loci may exert their effects via regulation of gene expression (Kim et al., 2014; Maurano et al., 2012). Thus, examining gene expression in relation to a cognitive endophenotype for schizophrenia may yield insights into genotypic effects on disease status and help to elucidate mechanisms by which cognitive dysfunction manifests in this disease. In the current study, we used a discordant twin design to identify genes differentially expressed in relation to verbal memory performance, a cognitive endophenotype for schizophrenia. Gene expression was assayed from peripheral blood mononuclear cells (PBMCs) – the most feasible way to assess expression levels in living patients. Gene expression in PBMCs is broadly heritable and correlates with central nervous system expression patterns (Cheung et al., 2003). While it is likely that some genes influencing memory performance will not be schizophrenia-related, given the endophenotypic pattern of the CVLT, which suggests shared genetic etiology between memory and schizophrenia, we expected some proportion of these memory-related genes to show differential expression by diagnostic status (Glahn et al., 2007; Greenwood et al., 2007; van Erp et al., 2008). This subset would represent a selection of genes potentially involved in those systems underlying memory impairment in schizophrenia. A twin design further allowed us to test the heritability of expression for each of these genes, dissociating potentially etiologically relevant genetic alterations from disease-related secondary effects.