Abstracts for the Sixth Biennial SIRS Conference Oral Session: Genetics S83 O4.2. HERITABILITY AND CORRELATION TO SCHIZOPHRENIA SPECTRUM DISORDER OF GLUTAMATE AND OTHER NEUROMETABOLITE LEVELS IN ANTERIOR CINGULATE AND LEFT THALAMUS: A REGISTER BASED MAGNETIC RESONANCE TWIN STUDY Christian Legind* ,1 , Brian Broberg 2 , Rene Mandl 3 , Rachel Brouwer 3 , Simon Anhøj 4 , Rikke Hilker 4 , Maria H. Jensen 4 , Philip McGuire 5 , Hilleke E. Hulshoff Pol 6 , Birgitte Fagerlund 7 , Egill Rostrup 8 , Birte Glenthoj 4 1 Psychiatric Center Glostrup; 2 Center for Neuropsychiatric Schizophrenia Research; 3 University Medical Center Utrecht; 4 Center for Neuropsychiatric Schizophrenia Research and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Copenhagen University Hospital, Mental Health Center Glostrup, 5 Institute of Psychiatry, Psychology & Neuroscience, King’s College London; 6 Brain Center Rudolf Magnus, University Medical Center Utrecht; 7 Center for Neuropsychiatric Schizophrenia Research, Psychiatric Center Glostrup, Mental Health Services Capital Region of Denmark, University of Copenhagen and The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH); 8 Center for Neuropsychiatric Schizophrenia Research, & Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Psychiatric Center Glostrup, University of Copenhagen, & Glostrup University Hospital Background: Glutamatergic changes in schizophrenia may precede dopamin- ergic alterations leading to psychopathology as part of a dopaminergic path- way, or they may represent a distinct pathophysiology. It is unknown if these glutamatergic alterations are due to genetic infuences, although fndings in gene studies implicate the NMDA receptor. Higher levels of glutamate and glutamine have been reported in the thalamus of patients with schizophrenia, while studies of the anterior cingulate cortex (ACC) have reported increased, decreased, and unaltered levels compared to healthy controls. By studying discordant mono- (MZ) and dizygotic (DZ) twins it is possible to estimate heritability and correlation to disease in the same population. This kind of study has only been done once on glutamate levels, but no heritability estimates were reported. 1 A study of older healthy twins found N-acetyl aspartate (NAA), choline (Cho), creatinine (Cr), and myo-inositol (MI) levels to be heritable in posterior cingulate cortex. 2 Of these metabo- lites, NAA has generally been found to correlate negatively with schizo- phrenia. Here we present our fnal results on heritability, and correlation to liability for schizophrenia spectrum disorder (ICD-10 F2x.x) of the neuro- metabolite levels in the ACC and the left thalamus. Methods: By linking The Danish Twin Register and The Danish Psychiatric Central Research Register, 25 complete MZ and 21 complete DZ twin pairs con- or discordant for schizophrenia spectrum disorder (ICD 10 F2x.x) and 29 complete MZ and 20 complete DZ healthy control pairs were included. Thirteen additional twins were scanned without their siblings. Spectra of glutamate, Glx, NAA, Cho, Cr and MI were obtained by [1H]-MR spec- troscopy at 3 tesla and analyzed by using LCModel. Additive genetic, common environmental and unique environmental effects on metabolite levels were calculated by structural equation modeling with openMX soft- ware. The best ftting model was determined by the Akaike Information Criterion. Results: In the ACC heritability estimates were signifcant for glutamate (29%), Glx (31%), NAA (39%), Cho (38%), Cr (37%) and MI (33%). In the left thalamus we found signifcant estimates of heritability for glutamate (16%), Glx (31%), Cho (60%), and of common environment for Cr (29%). A signifcant positive correlation to schizophrenia spectrum liability was found for glutamate in the left thalamus (r=0.16; p = 0.03), and negative correlations were found for NAA (r = -0.16; p = 0.02) and Cr (r = -0.25; p = 0.006) in the ACC. For glutamate in the thalamus and Cr in the ACC the signifcant correlation to disease was due to overlapping genetic effects infuencing both metabolite and disease. Discussion: In this the frst study to estimate heritability of glutamate levels in the brain, the primary fndings are that glutamate levels in both the ACC and the left thalamus are heritable, and in the left thalamus also correlated to disease with a signifcant genetic overlap. This emphasizes glutamate levels in the left thalamus as a potential endophenotypic marker for schiz- ophrenia. NAA and Cr were negatively correlated to disease in the ACC, which could point to disturbances of neuronal health and metabolism. For Cr an overlap of genes infuencing both metabolite levels and disease sug- gests Cr as a possible candidate endophenotype. References: 1. Lutkenhoff ES, van Erp TG, Thomas M a, Therman S, Manninen M, Huttunen MO et al. Proton MRS in twin pairs discordant for schizophre- nia. Mol Psychiatry 2010; 15: 308–18. 2. Batouli SAH, Sachdev PS, Wen W, Wright MJ, Suo C, Ames D et al. The heritability of brain metabolites on proton magnetic resonance spectros- copy in older individuals. Neuroimage 2012; 62: 281–289. O4.3. INCREASED CEREBRAL BLOOD FLOW AFTER SINGLE DOSE OF ANTIPSYCHOTICS IN HEALTHY SUBJECTS DEPENDS ON DOPAMINE D2 RECEPTOR DENSITY PROFILES EVALUATED WITH PET AND MRNA EXPRESSION DATA. Pierluigi Selvaggi* ,1 , Mattia Veronese 1 , Peter CT Hawkins 1 , Ottavia Dipasquale 1 , Gaia Rizzo 2 , Alessandro Bertolino 3 , Juergen Dukart 4 , Fabio Sambataro 5 , Steven CR Williams 1 , Federico Turkheimer 1 , Mitul Mehta 1 1 Institute of Psychiatry, Psychology and Neuroscience, King’s College London; 2 Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital; 3 University of Bari ‘Aldo Moro’; 4 Translational Medicine Neuroscience and Biomarkers, F. Hoffmann-La Roche Ltd, Basel, Switzerland; 5 University of Udine Background: Previous studies measuring cerebral blood fow (CBF) with magnetic resonance sequences like Arterial Spin Labelling (ASL) showed that patients with schizophrenia (SCZ) have increased CBF in basal gan- glia and reduced blood fow in cortical areas like the prefrontal cortex. It is still not clear whether these abnormalities are related to antipsychotic treat- ment or rather they refect a disease trait independent from medication. Interestingly, administration of single dose of antipsychotics in healthy volunteers produce marked functional effects that are in the same region reported as altered in SCZ. These effects are thought to depend on dopa- mine D2 receptor (D2R) blockade, although their relationship with anti- psychotic pharmacodynamics has not been fully established yet. In fact, the haemodynamic nature of CBF measures makes diffcult to interpret drug effects in terms of altered neurotransmission function. Here, we tested whether CBF changes induced by different antipsychotics mirror receptor distribution profles of D2R. We evaluated the correlation of CBF varia- tion with receptor density as measured with PET and brain mRNA expres- sion extracted from the Allen Human Brain Atlas (ABA). Methods: Forty-two healthy male subjects were enrolled in a double blind, randomized, placebo-controlled, crossover study. Participants were ran- domized in two equal parallel groups to receive a single dose of antipsy- chotic/placebo in three separate sessions. In Group 1 placebo, olanzapine 7.5mg (OLA) or haloperidol 3mg (HAL) were administered before the MRI scan. In Group 2 participants received placebo, 0.5mg (lowRIS) or 2mg (highRIS) of risperidone. Regional CBF was assessed with pseudo- continuous ASL (pCASL) sequence. For each antipsychotic, a paired T-test was performed in SPM12 with global CBF values as covariate of no interest.