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Original Investigation |

Polygenic Risk of Psychosis and Ventral Striatal Activation During Reward Processing in Healthy Adolescents

Thomas M. Lancaster, PhD1,2; David E. Linden, MD, PhD1,2,3; Katherine E. Tansey, PhD4; Tobias Banaschewski, MD, PhD5; Arun L. W. Bokde, PhD6; Uli Bromberg, Dipl-Psych7; Christian Büchel, MD7; Anna Cattrell, PhD8; Patricia J. Conrod, PhD9,10; Herta Flor, PhD11; Vincent Frouin, PhD12; Jürgen Gallinat, MD13; Hugh Garavan, PhD14; Penny Gowland, PhD15; Andreas Heinz, MD, PhD16; Bernd Ittermann, PhD17; Jean-Luc Martinot, MD, PhD18,19; Marie-Laure Paillère Martinot, MD, PhD18,19,20; Eric Artiges, MD, PhD18,21; Herve Lemaitre, PhD18,19; Frauke Nees, PhD22; Dimitri Papadopoulos Orfanos, PhD12; Tomáš Paus, MD, PhD22; Luise Poustka, MD23; Michael N. Smolka, MD24; Nora C. Vetter, PhD24; Sarah Jurk, Dipl-Psych24; Eva Mennigen, MD24; Henrik Walter, MD, PhD16; Robert Whelan, PhD25; Gunter Schumann, MD8 ; for the IMAGEN Consortium
[+] Author Affiliations
1Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom
2Cardiff University Brain Imaging Research Centre, Cardiff University, Cardiff, United Kingdom
3MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff School of Medicine, Cardiff University, Cardiff, United Kingdom
4MRC Integrative Epidemiology Unit, School of Social and Community Medicine, Faculty of Medicine and Dentistry, University of Bristol, Bristol, United Kingdom
5Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
6Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
7University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
8MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King’s College, London, United Kingdom
9Department of Psychiatry, Universite de Montreal, CHU Ste Justine Hospital, Montreal, Quebec, Canada
10Department of Psychological Medicine and Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience, King's College, London, United Kingdom
11Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
12Neurospin, Commissariat à l'Energie Atomique, Paris, France
13Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
14Departments of Psychiatry and Psychology, University of Vermont, Burlington
15Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, Nottingham, United Kingdom
16Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin, Berlin, Germany
17Physikalisch-Technische Bundesanstalt, Berlin, Germany
18Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1000, Neuroimaging and Psychiatry Research Unit, University Paris-Sud, Orsay, France
19University Paris Descartes, Sorbonne Paris Cité, Paris, France
20Assistance Publique–Hôpitaux de Paris, Maison de Solenn, Cochin Hospital, Paris, France
21Orsay Hospital, Orsay, France
22Rotman Research Institute, Baycrest Health Sciences, and Departments of Psychology and Psychiatry, University of Toronto, Toronto, Ontario, Canada
23Department of Child and Adolescent Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
24Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany
25Department of Psychology, University College Dublin, Dublin, Ireland
JAMA Psychiatry. 2016;73(8):852-861. doi:10.1001/jamapsychiatry.2016.1135.
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Importance  Psychotic disorders are characterized by attenuated activity in the brain’s valuation system in key reward processing areas, such as the ventral striatum (VS), as measured with functional magnetic resonance imaging.

Objective  To examine whether common risk variants for psychosis are associated with individual variation in the VS.

Design, Setting, and Participants  A cross-sectional study of a large cohort of adolescents from the IMAGEN study (a European multicenter study of reinforcement sensitivity in adolescents) was performed from March 1, 2008, through December 31, 2011. Data analysis was conducted from October 1, 2015, to January 9, 2016. Polygenic risk profile scores (RPSs) for psychosis were generated for 1841 healthy adolescents. Sample size and characteristics varied across regression analyses, depending on mutual information available (N = 1524-1836).

Main Outcomes and Measures  Reward-related brain function was assessed with blood oxygen level dependency (BOLD) in the VS using the monetary incentive delay (MID) task, distinguishing reward anticipation and receipt. Behavioral impulsivity, IQ, MID task performance, and VS BOLD were regressed against psychosis RPS at 4 progressive P thresholds (P < .01, P < .05, P < .10, and P < .50 for RPS models 1-4, respectively).

Results  In a sample of 1841 healthy adolescents (mean age, 14.5 years; 906 boys and 935 girls), we replicated an association between increasing psychosis RPS and reduced IQ (matrix reasoning: corrected P = .003 for RPS model 2, 0.4% variance explained), supporting the validity of the psychosis RPS models. We also found a nominally significant association between increased psychosis RPS and reduced MID task performance (uncorrected P = .03 for RPS model 4, 0.2% variance explained). Our main finding was a positive association between psychosis RPS and VS BOLD during reward anticipation at all 4 psychosis RPS models and for 2 P thresholds for reward receipt (RPS models 1 and 3), correcting for the familywise error rate (0.8%-1.9% variance explained).

Conclusions and Relevance  These findings support an association between psychosis RPS and VS BOLD in adolescents. Genetic risk for psychosis may shape an individual’s response to rewarding stimuli.

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Coronal Sections at Montreal Neurological Institute Coordinate y = 5

Positive associations between the psychosis risk profile score (RPS) and blood oxygen level dependency (BOLD) in the ventral striatum (VS) during reward anticipation and reward receipt at 4 progressive P thresholds (P < .01 for RPS model 1, P < .05 for RPS model 2, P < .10 for RPS model 3, and P < .50 for RPS model 4), controlling for age, sex, testing site, Wechsler Intelligence Scale for Children–Fourth Edition variables, and the first 5 principal components (n = 1528 and 1559, respectively). All clusters are corrected for the familywise error across the bilateral VS (P < .05). Plots on the right show the mean psychosis RPSs across 10 deciles plotted against BOLD parameter estimates in the significant clusters identified in the multiple regression. Note that the 10 deciles reflect the data extracted from the clusters within the VS, which remained significant and are purely for illustration purposes. Error bars indicate 95% CI. AU indicates arbitrary units; L, left hemisphere; NS, nonsignificant.

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