As one example, executive dysfunction spans diagnostic taxons; a genetic variant perturbing GDC-0449 mw frontoparietal connectivity would, almost necessarily, increase susceptibility to multiple disorders, because the resulting deficits in executive function are not disorder specific. While it would still be a simplification to assume that genetic variants have an impact on only one such circuit (Meyer-Lindenberg and Weinberger, 2006), this model proposes that pleiotropic effects on symptom clusters are consistently mediated

by circuits associated with these clusters across diagnostic categories. Our proposal is grounded in the assumption that genetic factors significantly contribute to psychopathology-linked patterns of altered connectivity. If this assumption is valid, measures of functional connectivity should show significant heritability. The evidence supports this. For example, the unaffected siblings of patients with schizophrenia show alterations in frontoparietal connectivity that mirror EGFR inhibitor changes seen in illness (Woodward et al., 2009 and Rasetti et al., 2011). Further, a recent linkage analysis in 29 extended pedigrees confirms the heritability of resting-state DMN connectivity (Glahn et al., 2010). These findings confirm that genetic factors shape connectivity in networks

linked to symptom domains, and imply that connectivity changes observed in mental disorders reflect a cause, rather than a consequence, of being ill. Of course, Dichloromethane dehalogenase this concept can be easily extended to other causal factors associated with mental illness, in particular, environmental or epigenetic effects. Genetic imaging studies support the idea that heritable differences in brain connectivity contribute to the dimensionality of mental illness. Here, we unpack this concept by detailing

connectivity findings for several well-characterized pleiotropic genetic variants. A functional coding variant (rs4680; val158met) within the gene encoding the dopamine catabolic enzyme catechol-o-methyltransferase (COMT) has been shown to exert pleiotropic effects on cognition, mood, and related disorders. The 158val allele, linked to increased enzyme stability and lower dopamine levels in brain, has modest associations to psychotic disorders and cognitive performance (Allen et al., 2008 and Goldman et al., 2009), and strong associations to prefrontal function during cognitive tasks (Mier et al., 2010). The 158met allele, linked to decreased enzyme stability and higher dopamine levels in brain, has modest associations to substance abuse, mood disorders, and anxiety disorders and strong associations to corticolimbic function during affective tasks (Stein et al., 2005, Pooley et al., 2007, Lohoff et al., 2008, Kolassa et al., 2010, Mier et al., 2010 and Åberg et al., 2011).