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Science 1 May 2009:
Vol. 324. no. 5927, p. 605
DOI: 10.1126/science.1167768
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Brevia

Neural Mechanisms of a Genome-Wide Supported Psychosis Variant

Christine Esslinger,1,* Henrik Walter,2,3,* Peter Kirsch,1,* Susanne Erk,3 Knut Schnell,2,3 Claudia Arnold,3 Leila Haddad,1 Daniela Mier,1 Carola Opitz von Boberfeld,3 Kyeon Raab,1 Stephanie H. Witt,4 Marcella Rietschel,4 Sven Cichon,5 Andreas Meyer-Lindenberg1,{dagger}

Schizophrenia is a devastating, highly heritable brain disorder of unknown etiology. Recently, the first common genetic variant associated on a genome-wide level with schizophrenia and possibly bipolar disorder was discovered in ZNF804A (rs1344706). We show, by using an imaging genetics approach, that healthy carriers of rs1344706 risk genotypes exhibit no changes in regional activity but pronounced gene dosage–dependent alterations in functional coupling (correlated activity) of dorsolateral prefrontal cortex (DLPFC) across hemispheres and with hippocampus, mirroring findings in patients, and abnormal coupling of amygdala. Our findings establish disturbed connectivity as a neurogenetic risk mechanism for psychosis supported by genome-wide association, show that rs1344706 or variation in linkage disequilibrium is functional in human brain, and validate the intermediate phenotype strategy in psychiatry.

1 Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, J5, 68159 Mannheim, Germany.
2 Division of Medical Psychology, University of Bonn, 53105 Bonn, Germany.
3 Department of Psychiatry and Psychotherapy, University of Bonn, 53105 Bonn, Germany.
4 Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, J5, 68159 Mannheim, Germany.
5 Department of Genomics, Life and Brain Center and Institute of Human Genetics, University of Bonn, 53105 Bonn, Germany.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: a.meyer-lindenberg{at}zi-mannheim.de

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