title: Identification of gene ontologies linked to prefrontal-hippocampal functional coupling in the human brain.
abstract: Functional interactions between the dorsolateral prefrontal cortex and hippocampus during working memory have been studied extensively as an intermediate phenotype for schizophrenia. Coupling abnormalities have been found in patients, their unaffected siblings, and carriers of common genetic variants associated with schizophrenia, but the global genetic architecture of this imaging phenotype is unclear. To achieve genome-wide hypothesis-free identification of genes and pathways associated with prefrontal-hippocampal interactions, we combined gene set enrichment analysis with whole-genome genotyping and functional magnetic resonance imaging data from 269 healthy German volunteers. We found significant enrichment of the synapse organization and biogenesis gene set. This gene set included known schizophrenia risk genes, such as neural cell adhesion molecule (NRCAM) and calcium channel, voltage-dependent, beta 2 subunit (CACNB2), as well as genes with well-defined roles in neurodevelopmental and plasticity processes that are dysfunctional in schizophrenia and have mechanistic links to prefrontal-hippocampal functional interactions. Our results demonstrate a readily generalizable approach that can be used to identify the neurogenetic basis of systems-level phenotypes. Moreover, our findings identify gene sets in which genetic variation may contribute to disease risk through altered prefrontal-hippocampal functional interactions and suggest a link to both ongoing and developmental synaptic plasticity.
authors: Departments of Psychiatry and Psychotherapy and.
authors: Luanna
authors: L
authors: Dixson
authors: Department of Psychiatry, Division of Mind and Brain Research, Charité Campus Mitte, 10117 Berlin, Germany;
authors: Henrik
authors: H
authors: Walter
authors: Departments of Psychiatry and Psychotherapy and.
authors: Michael
authors: M
authors: Schneider
authors: Department of Psychiatry, Division of Mind and Brain Research, Charité Campus Mitte, 10117 Berlin, Germany;
authors: Susanne
authors: S
authors: Erk
authors: Departments of Psychiatry and Psychotherapy and.
authors: Axel
authors: A
authors: Schäfer
authors: Departments of Psychiatry and Psychotherapy and.
authors: Leila
authors: L
authors: Haddad
authors: Departments of Psychiatry and Psychotherapy and.
authors: Oliver
authors: O
authors: Grimm
authors: Department of Genomics, Life and Brain Center,Institute of Human Genetics, andInstitute for Genomic Mathematics, University of Bonn, 53127 Bonn, Germany.
authors: Manuel
authors: M
authors: Mattheisen
authors: Department of Genomics, Life and Brain Center,Institute of Human Genetics, andInstitute for Genomic Mathematics, University of Bonn, 53127 Bonn, Germany.
authors: Markus M
authors: MM
authors: Nöthen
authors: Department of Genomics, Life and Brain Center,Institute of Human Genetics, and.
authors: Sven
authors: S
authors: Cichon
authors: Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany;
authors: Stephanie H
authors: SH
authors: Witt
authors: Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany;
authors: Marcella
authors: M
authors: Rietschel
authors: Department of Psychiatry, Division of Mind and Brain Research, Charité Campus Mitte, 10117 Berlin, Germany;
authors: Sebastian
authors: S
authors: Mohnke
authors: Department of Psychiatry, Division of Mind and Brain Research, Charité Campus Mitte, 10117 Berlin, Germany;
authors: Nina
authors: N
authors: Seiferth
authors: Department of Psychiatry, Division of Mind and Brain Research, Charité Campus Mitte, 10117 Berlin, Germany;
authors: Andreas
authors: A
authors: Heinz
authors: Departments of Psychiatry and Psychotherapy and.
authors: Heike
authors: H
authors: Tost
authors: Departments of Psychiatry and Psychotherapy and a.meyer-lindenberg@zi-mannheim.de.
authors: Andreas
authors: A
authors: Meyer-Lindenberg
mesh_terms: D020746:Calcium Channels, L-Type / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D063132:Connectome; D063990:Gene Ontology; D005838:Genotype; D005858:Germany; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008570:Memory, Short-Term / Q000502:physiology*; D010641:Phenotype; D017397:Prefrontal Cortex / Q000502:physiology*; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology
chemical_list: C107597:CACNB2 protein, human; D020746:Calcium Channels, L-Type; D015815:Cell Adhesion Molecules; C491152:NRCAM protein, human
keywords: GSEA; endophenotype; functional connectivity; genetic risk variants