title: Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes.
abstract: Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high- versus low-risk constellation regarding the accumulation model. Thereby, the brain-expressed miR-181 species emerged as potential "umbrella regulator", with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes.
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Beata
authors.initials: B
authors.lastname: Stepniak
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Kästner
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Giulia
authors.initials: G
authors.lastname: Poggi
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Mitjans
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Begemann
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Halle, Halle, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Van der Auwera
authors.affiliation: Epigenetics in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
authors.forename: Farahnaz
authors.initials: F
authors.lastname: Sananbenesi
authors.affiliation: Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Dilja
authors.initials: D
authors.lastname: Krueger-Burg
authors.affiliation: Molecular Neuroplasticity, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Matuszko
authors.affiliation: Department of Biochemistry, University of Würzburg, Würzburg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Brosi
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.affiliation: Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Fritz
authors.initials: F
authors.lastname: Benseler
authors.affiliation: KU Leuven, Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, Leuven, Belgium Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bagni
authors.affiliation: Department of Biochemistry, University of Würzburg, Würzburg, Germany.
authors.forename: Utz
authors.initials: U
authors.lastname: Fischer
authors.affiliation: Molecular Neuroplasticity, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dityatev
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Hans-Jörgen
authors.initials: HJ
authors.lastname: Grabe
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Halle, Halle, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: Epigenetics in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Department of Psychiatry & Psychotherapy, University of Göttingen, Göttingen, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany ehrenreich@em.mpg.de.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
mesh_terms: D001321:Autistic Disorder / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C497683:FMR1 protein, human; C096916:FXR1 protein, human; C096915:FXR2 protein, human; C540193:MIrn181 microRNA, human
keywords: FMR1; FMR2; FXR1; FXR2; PGAS; miR‐181