The group has continued to make strides in imaging genetics in healthy volunteers, patients with schizophrenia and their unaffected siblings. Using fMRI, Callicott et al. (J Clin Invest., 2013) extended findings from a previous and novel translational experiment regarding genetic factors that regulate and alter hippocampal developmental trajectory, DISC1 and NKCC1. These data highlight the importance of epistatic models in understanding genetic association with complex brain phenotypes and also the power of replication. Replication was also key to the work of Tost and colleagues (J Neurosci,2014) showed that BOLD fMRI and working memory effect of NRG3, previously associated with novel splice form expression, was associated with prefrontal. In another translational study, Papaleo and colleagues (Mol Psychiatry, 2014) used BOLD fMRI during working memory to explore the gene-gene interaction between two classic schizophrenia candidate genes -- DISC1 and DTNBP1-- in healthy subjects during working memory studied with fMRI. From genome-wide association to general intelligence, Dickinson and colleagues (JAMA Psychiatry, 2014) also showed a relationship of SCN2A to prefrontal cortex activity using BOLD fMRI in patients with schizophrenia and healthy subjects. Again moving from post-mortem expression to in vivo function, Morita, Callicott and colleagues (J Neurosci, 2014) showed that variation within NKCC1 related to transcript expression was also associated with working memory, general cognition and fMRI activation. Magalona and colleagues (CNS Drugs, 2013) demonstrated that tolcapone (a COMT inhibitor) modulated activity in the anterior cingulate during an event-related mental flexibility task (the VAC task) in healthy young people. Interesting findings have emerged in the field of cognitive aging. Muse and colleagues investigated episodic memory (EM) decline in aging and found the rate of decline associated with the single nucleotide polymorphism (rs17070145) in the WWC1 gene encoding the KIBRA protein critical for long-term potentiation and memory consolidation using functional magnetic resonance imaging (fMRI). Finally, Rasetti and colleagues (JAMA Psychiatry, 2014) identified a potential novel intermediate or endophenotype relevant to schizophrenia using an encoding task. In the last year, abstracts have been presented at several international meetings and the related manuscripts are in the late stages of preparation. We have data indicating that GABA levels in the anterior cingulate cortex are subtly decreased in patients with schizophrenia as compared to controls, while unaffected siblings have more marked reductions. Glutamate levels appear to be unchanged in treated and untreated patients with schizophrenia as compared to controls, as well as in unaffected siblings. We also studied the effects of suspension of neuroleptic medication on GABA levels in patients with schizophrenia, finding no apparent effect. A preliminary finding conducted on 15 patients who had been scanned during psychotropic suspension and during active single neuroleptic treatment indicates that the levels of glutamate while off medications may be predictive of neuroleptic response, while GABA levels are not. With DTI, we found an effect of a polymorphism in the serotonin transporter promoter region (5HTT-LPR) on the white matter microstructure of the uncinate fasciculus. This polymorphism has been implicated in the causation of mood disorders and has been previously associated with changes in white matter microstructure, though some results have been conflicting. We implemented a novel method to define the uncinate fasciculus that allows for automatic delineation of multiple white matter tracts and extraction of tract metrics. delineation of multiple white matter tracts and extraction of tract metrics. The work on obstetrical complications as an environmental risk factor for schizophrenia generated a publication (Jaffe et al. 2014, Mol. Psych.) showing that it is unlikely that de novo mutations are the main cause for the known association of paternal age and schizophrenia. Obstetrical complications were associated with increased risk for schizophrenia especially for lower birth order, consistent with the fact that initial pregnancies are more likely to be problematic than later ones. Further data on obstetrical complications and their interaction with genetic risk are currently being analyzed in collaboration with Dr. Weinberger at the Lieber Institute for Brain Development. Effects of urban upbringing (a risk factor for schizophrenia) on brain activation during a working memory task and interactions with genetic variation in catechol-O-methyltransferase (COMT Val158Met polymorphism) were also studied. Urban upbringing resulted in reduced efficiency of activation, and there was a significant interaction with the COMT Val158Met polymorphism, where the individuals reared in rural environments with a Val/Val COMT genotype were least efficient, while Met Carriers were least efficient among the participants raised in a large city. A recent finding in collaboration was based on relaxometry techniques and showed an increase in myelin water fraction in the medial temporal lobe and in the cerebellar white matter. Additionally, through our collaboration on Williams syndrome, we have laid the groundwork for determination of white matter tract volume in large datasets of individuals for genetic studies. We focused on the inferior fronto-occipital fasciculus because preliminary work indicated that this might be the white matter tract particularly reduced in volume in participants with short deletions of the Williams syndrome chromosome region.
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