title: Genetic variation of the RASGRF1 regulatory region affects human hippocampus-dependent memory.
abstract: The guanine nucleotide exchange factor RASGRF1 is an important regulator of intracellular signaling and neural plasticity in the brain. RASGRF1-deficient mice exhibit a complex phenotype with learning deficits and ocular abnormalities. Also in humans, a genome-wide association study has identified the single nucleotide polymorphism (SNP) rs8027411 in the putative transcription regulatory region of RASGRF1 as a risk variant of myopia. Here we aimed to assess whether, in line with the RASGRF1 knockout mouse phenotype, rs8027411 might also be associated with human memory function. We performed computer-based neuropsychological learning experiments in two independent cohorts of young, healthy participants. Tests included the Verbal Learning and Memory Test (VLMT) and the logical memory section of the Wechsler Memory Scale (WMS). Two sub-cohorts additionally participated in functional magnetic resonance imaging (fMRI) studies of hippocampus function. 119 participants performed a novelty encoding task that had previously been shown to engage the hippocampus, and 63 subjects participated in a reward-related memory encoding study. RASGRF1 rs8027411 genotype was indeed associated with memory performance in an allele dosage-dependent manner, with carriers of the T allele (i.e., the myopia risk allele) showing better memory performance in the early encoding phase of the VLMT and in the recall phase of the WMS logical memory section. In fMRI, T allele carriers exhibited increased hippocampal activation during presentation of novel images and during encoding of pictures associated with monetary reward. Taken together, our results provide evidence for a role of the RASGRF1 gene locus in hippocampus-dependent memory and, along with the previous association with myopia, point toward pleitropic effects of RASGRF1 genetic variations on complex neural function in humans.
authors.affiliation: Department of Behavioral Neurology and Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology Magdeburg, Germany.
authors.forename: Adriana
authors.initials: A
authors.lastname: Barman
authors.affiliation: Department of Behavioral Neurology and Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology Magdeburg, Germany ; Otto von Guericke University Magdeburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Assmann
authors.affiliation: Department of Clinical Psychology, University of Salzburg Salzburg, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Richter
authors.affiliation: Department of Behavioral Neurology and Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology Magdeburg, Germany ; Otto von Guericke University Magdeburg, Germany ; Bernstein Center for Computational Neuroscience, Humboldt University Berlin, Germany.
authors.forename: Joram
authors.initials: J
authors.lastname: Soch
authors.affiliation: Institute of Cognitive Neurology and Dementia Research, Otto von Guericke University Magdeburg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Schütze
authors.affiliation: Department of Psychiatry, Charité Universitätsmedizin Berlin Berlin, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Wüstenberg
authors.affiliation: Department of Behavioral Neurology and Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology Magdeburg, Germany ; Otto von Guericke University Magdeburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Deibele
authors.affiliation: Department of Behavioral Neurology and Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology Magdeburg, Germany ; Department of Genetics, Radboud University Nijmegen Medical Center Nijmegen, Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Klein
authors.affiliation: Department of Behavioral Neurology and Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology Magdeburg, Germany.
authors.forename: Anni
authors.initials: A
authors.lastname: Richter
authors.affiliation: Department of Behavioral Neurology and Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology Magdeburg, Germany.
authors.forename: Gusalija
authors.initials: G
authors.lastname: Behnisch
authors.affiliation: Institute of Cognitive Neurology and Dementia Research, Otto von Guericke University Magdeburg, Germany ; Helmholtz Center for Neurodegenerative Diseases Magdeburg, Germany ; Center for Behavioral Brain Sciences Magdeburg, Germany.
authors.forename: Emrah
authors.initials: E
authors.lastname: Düzel
authors.affiliation: Department of Human Genetics, Otto von Guericke University Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.affiliation: Department of Behavioral Neurology and Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology Magdeburg, Germany ; Center for Behavioral Brain Sciences Magdeburg, Germany.
authors.forename: Constanze I
authors.initials: CI
authors.lastname: Seidenbecher
authors.affiliation: Department of Behavioral Neurology and Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology Magdeburg, Germany ; Department of Psychiatry, Charité Universitätsmedizin Berlin Berlin, Germany ; Center for Behavioral Brain Sciences Magdeburg, Germany ; Department of Neurology, Otto von Guericke University Magdeburg, Germany.
authors.forename: Björn H
authors.initials: BH
authors.lastname: Schott
keywords: RASGRF1; episodic memory; fMRI; genetic variation; hippocampus