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Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes.

Authors
  • Stepniak, Beata1
  • Kästner, Anne2
  • Poggi, Giulia1
  • Mitjans, Marina1
  • Begemann, Martin1
  • Hartmann, Annette3
  • Van der Auwera, Sandra4
  • Sananbenesi, Farahnaz5
  • Krueger-Burg, Dilja6
  • Matuszko, Gabriela7
  • Brosi, Cornelia8
  • Homuth, Georg9
  • Völzke, Henry10
  • Benseler, Fritz6
  • Bagni, Claudia11
  • Fischer, Utz8
  • Dityatev, Alexander7
  • Grabe, Hans-Jörgen4
  • Rujescu, Dan3
  • Fischer, Andre12
  • And 1 more
  • 1 Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
  • 2 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.
  • 3 Department of Psychiatry and Psychotherapy, University of Halle, Halle, Germany.
  • 4 Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
  • 5 Epigenetics in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
  • 6 Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
  • 7 Molecular Neuroplasticity, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
  • 8 Department of Biochemistry, University of Würzburg, Würzburg, Germany.
  • 9 Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
  • 10 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
  • 11 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.
  • 12 Epigenetics in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Department of Psychiatry & Psychotherapy, University of Göttingen, Göttingen, Germany.
  • 13 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 [email protected]
Type
Published Article
Journal
EMBO Molecular Medicine
Publisher
EMBO
Publication Date
December 2015
Volume
7
Issue
12
Pages
1565–1579
Identifiers
DOI: 10.15252/emmm.201505696
PMID: 26612855
Source
Medline
Keywords
License
Unknown

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.

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