title: Functional neuroimaging effects of recently discovered genetic risk loci for schizophrenia and polygenic risk profile in five RDoC subdomains.
abstract: 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 (PFWE(ROI)=0.047) and social cognition (PFWE(ROI)=0.025), respectively. Single SNP analyses revealed that rs9607782, located near EP300, was significantly associated with amygdala recruitment during emotion processing (PFWE(ROI)=1.63 × 10-4, surpassing Bonferroni correction for the number of SNPs). Importantly, this association was replicable in an independent sample (N=150; PFWE(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.
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.|Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Erk
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.|Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Mohnke
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.|Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ripke
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.|Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: T A
authors.initials: TA
authors.lastname: Lett
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.|Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: I M
authors.initials: IM
authors.lastname: Veer
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.|Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Wackerhagen
authors.affiliation: Department of Psychiatry, Psychosomatic Medicine, Psychotherapy, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Grimm
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Romanczuk-Seiferth
authors.affiliation: Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Tost
authors.affiliation: Department of Biomedicine, University of Aarhus, Aarhus, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Institute of Neuroscience and Medicine, Research Centre Jülich, Jülich, Germany.|Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: T W
authors.initials: TW
authors.lastname: Mühleisen
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Charlet
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.|Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Skarabis
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Kiefer
authors.affiliation: Institute of Neuroscience and Medicine, Research Centre Jülich, Jülich, Germany.|Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: S H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.|Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Walter
mesh_terms: D000679:Amygdala / Q000000981:diagnostic imaging / Q000503:physiopathology; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology*; D004644:Emotions; D059907:Functional Neuroimaging; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging / Q000503:physiopathology; D064368:Healthy Volunteers; D006801:Humans; D008279:Magnetic Resonance Imaging; D061212:Memory, Episodic; D008570:Memory, Short-Term; D020412:Multifactorial Inheritance; D010296:Parietal Lobe / Q000000981:diagnostic imaging / Q000503:physiopathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012201:Reward; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D012565:Schizophrenic Psychology; D012938:Social Perception