Manuel Mattheisen

Functional neuroimaging effects of recently discovered genetic risk loci for schizophrenia and polygenic risk profile in five RDoC subdomains

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • S. Erk, Charite Univ Med Berlin, Charite Medical University of Berlin, Humboldt University of Berlin, Free University of Berlin, Div Mind & Brain Res
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  • S. Mohnke, Charite Univ Med Berlin, Charite Medical University of Berlin, Humboldt University of Berlin, Free University of Berlin, Div Mind & Brain Res
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  • S. Ripke, Harvard Med Sch, Harvard University, Dept Hlth Care Policy
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  • T. A. Lett, Charite Univ Med Berlin, Charite Medical University of Berlin, Humboldt University of Berlin, Free University of Berlin, Div Mind & Brain Res
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  • I. M. Veer, Charite Univ Med Berlin, Charite Medical University of Berlin, Humboldt University of Berlin, Free University of Berlin, Div Mind & Brain Res
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  • C. Wackerhagen, Charite Univ Med Berlin, Charite Medical University of Berlin, Humboldt University of Berlin, Free University of Berlin, Div Mind & Brain Res
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  • O. Grimm, Goethe Univ Frankfurt, Goethe University Frankfurt, Dept Psychiat, Psychosomat Med, Psychotherapy
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  • N. Romanczuk-Seiferth, Charite Univ Med Berlin, Humboldt University of Berlin, Charite Medical University of Berlin, Free University of Berlin, Dept Psychiat & Psychotherapy
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  • F. Degenhardt, Univ Bonn, University of Bonn, Inst Human Genet
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  • H. Tost, Heidelberg Univ, Ruprecht Karl University Heidelberg, Fac Med Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy
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  • M. Mattheisen
  • T. W. Muehleisen, Univ Basel, University of Basel, Dept Biomed, Div Med Genet
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  • K. Charlet, Charite Univ Med Berlin, Humboldt University of Berlin, Charite Medical University of Berlin, Free University of Berlin, Dept Psychiat & Psychotherapy
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  • N. Skarabis, Charite Univ Med Berlin, Charite Medical University of Berlin, Humboldt University of Berlin, Free University of Berlin, Div Mind & Brain Res
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  • F. Kiefer, Heidelberg Univ, Ruprecht Karl University Heidelberg, Fac Med Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy
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  • S. Cichon, Univ Basel, University of Basel, Dept Biomed, Div Med Genet
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  • S. H. Witt, Heidelberg Univ, Ruprecht Karl University Heidelberg, Fac Med Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat
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  • M. M. Noethen, Univ Bonn, University of Bonn, Inst Human Genet
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  • M. Rietschel, Heidelberg Univ, Ruprecht Karl University Heidelberg, Fac Med Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat
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  • A. Heinz, Charite Univ Med Berlin, Humboldt University of Berlin, Charite Medical University of Berlin, Free University of Berlin, Dept Psychiat & Psychotherapy
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  • A. Meyer-Lindenberg, Heidelberg Univ, Ruprecht Karl University Heidelberg, Fac Med Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy
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  • H. Walter, Charite Univ Med Berlin, Charite Medical University of Berlin, Humboldt University of Berlin, Free University of Berlin, Div Mind & Brain Res

Recently, 125 loci with genome-wide support for association with schizophrenia were identified. We investigated the impact of these variants and their accumulated genetic risk on brain activation in five neurocognitive domains of the Research Domain Criteria (working memory, reward processing, episodic memory, social cognition and emotion processing). In 578 healthy subjects we tested for association (i) of a polygenic risk profile score (RPS) including all single-nucleotide polymorphisms (SNPs) reaching genome-wide significance in the recent genome-wide association studies (GWAS) meta-analysis and (ii) of all independent genome-wide significant loci separately that showed sufficient distribution of all allelic groups in our sample (105 SNPs). The RPS was nominally associated with perigenual anterior cingulate and posterior cingulate/precuneus activation during episodic memory (P-FWE(ROI) = 0.047) and social cognition (P-FWE(ROI) = 0.025), respectively. Single SNP analyses revealed that rs9607782, located near EP300, was significantly associated with amygdala recruitment during emotion processing (P-FWE(ROI) = 1.63 x 10(-4), surpassing Bonferroni correction for the number of SNPs). Importantly, this association was replicable in an independent sample (N = 150; (P-FWE(ROI) <0.025). Other SNP effects previously associated with imaging phenotypes were nominally significant, but did not withstand correction for the number of SNPs tested. To assess whether there was true signal within our data, we repeated single SNP analyses with 105 randomly chosen non-schizophrenia-associated variants, observing fewer significant results and lower association probabilities. Applying stringent methodological procedures, we found preliminary evidence for the notion that genetic risk for schizophrenia conferred by rs9607782 may be mediated by amygdala function. We critically evaluate the potential caveats of the methodological approaches employed and offer suggestions for future studies.

Original languageEnglish
Article number997
JournalTranslational Psychiatry
Volume7
Number of pages9
ISSN2158-3188
DOIs
Publication statusPublished - 10 Jan 2017

    Research areas

  • BIPOLAR DISORDER, INTERMEDIATE PHENOTYPE, IMAGING GENETICS, SOCIAL COGNITION, COMMON VARIATION, BRAIN-FUNCTION, VARIANT, HIPPOCAMPAL, PSYCHOSIS, CACNA1C

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